bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of the IL‐12/IL‐12R axis: a critical step in T‐helper cell differentiation and effector function
Authors: Sinigaglia Francesco , D'Ambrosio Daniele , Panina‐Bordignon Poola , Rogge Lars
Published: April 2006

Summary: Interleukin (IL)‐12 is required for the development of T‐helper (Th)1 cells, which have been shown to be important for protective cell‐mediated immune responses against a variety of intracellular pathogens. Recent studies have clarified the sources and the regulation ofIL‐12 production leading to Th1 development against microbes. Expression of IL‐12R is necessary for maintaining IL‐12 responsiveness and controlling Thl lineage commitment. Advances in this area have included a broader understanding of the factors involved in the regulation of the IL‐12Rβ2 signaling component. Expression of this receptor subunit in humans is critically influenced by IL‐12 and type I interferons. IL‐12 signaling results in STAT4 activation and interferon (IFN)‐γ production. Recent evidence suggests that IL‐12 also modulates a number of genes involved in leukocyte trafficking. Thus, IL‐12 is not only an important proinflammatory cytokine, which induces production of IFN‐γ and subsequent activation of phago‐cytic cells but also plays a major role in regulating the migration and proper positioning of effector cells.
The diversity of T‐cell co‐stimulation in the induction of antitumor immunity
Authors: Schlom Jeffrey , Hodse James W.
Published: April 2006

Summary: T‐cell activation has now been shown to require at least two signals. The first signal is antigen‐specific, is delivered through the T‐cell receptor (TCR) via the peptide/major histocompatibility complex (MHC). and causes the T cell to enter the ceil cycle. The second, or co‐stimulatory, signal is required for cytokine production and proliferation, and is mediated through ligand interaction on the surface of the T cell. This chapter deals with: 1) comparative studies on the use of a dual‐gene construct of a recombinant vaccinia (rV) vector containing a tumor‐associated antigen (TAA) gene and a co‐stimulatory molecule gene vs che use of admixtures of rV‐TAA and rV containing the co‐stimulatory molecule to induce and‐tumor immunity; 2) the use of an admixture of vaccinia viruses containing a lAA gene and the B7‐1 co‐stimulatory molecule gene to induce a therapeutic response in a lung metastasis tumor model: 3) the antitumor efficacy of whole‐tutnor‐cell vaccines in which the B7‐1 co‐stimulatory molecule is expressed in a tumor‐cell vaccine via a vaccinia vs a retroviral vector; 4) the use of recombinant poxviruses containing the genes for the co‐stimulatory molecules tCAM‐l or LFA‐3 to induce antitumor immunity: and 5) the use of poxvirus vectors containing a triad of co‐stimulatory molecules (B7‐1. ICAM‐1 and LFA‐3) that synergize to enhance both CD4+ and CD8+ T‐cell responses to a new threshold.
Human tumor antigens for cancer vaccine development
Authors: Wang Rong‐Fu , Rosenberg Steven A.
Published: April 2006

Summary: The adoptive transfer of tumor‐infiltrating lymphocytes (TH.) along with interleukin (H.)‐2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression. In the last few years, efforts have been made towards understanding the molecular basis of T‐cell‐mediated antitumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Tumor antigens identified thus far could be classified into several catagories: tissue‐specific differentiation antigens, tumor‐specific shared antigens and tumor‐specific unique antigens, CD4 T cells play a central role in orchestrating the host immune response against cancer, infections diseases, and autoimmune deseases, and we thus have attempted to identify major histocompatibility complex (MHC) class II‐restricted tumor antigens as well. The identification of tumor rejection antigens provides new opportunities for the development of therapeutic strategies against cancer. This review will summarize the current status of MHC class I‐ and class II‐restricted human tumor antigens, and their potential application to cancer treatment.
B‐cell malignancies as a model for cancer vaccines: from prototype protein to next generation genetic chemokine fusions
Authors: Biragyn Arya , Kwak Larry W.
Published: April 2006

Summary: B‐cell malignancy‐derived Ig may be considered a model tumor antigen for vaccine development. However, as a non‐immunogenic self antigen, it must also be first rendered immunogenic by chemical or genetic fusion to carriers which enable the induction of protective anti‐tumor immunity in murine tumor models. Our group has demonstrated chat active immunizations of human patients with idiotypic vaccines elicited antigen‐specific CD8+ T‐cell responses and antitumor effects. Several alternative preclinical strategies to develop vaccines have been previously reported, including fusion of tumor idiotype‐derived single chain Fv with cytokities and immunogenic peptides. On the other hand, we have recently explored a different approach in which the model antigen is rendered immunogenic in mice by genetically fusing it to a chemokine moiety. Administration of these vaccines as fusion proteins or naked DNA vaccines may allow efficient targeting of antigen‐presenting cells in vivo. Potent autitumor immunity was dependent on the generation of specific anti‐idiotypic antibodies and both CD4+ and CD8+ effector T cells. We propose that chemokine fusion may represent a novel, general strategy for formulating existing or newly identified tumor and HIV antigens into vaccines for cancer and AIDS, respectively, which elicit potent CD8+ T‐cell immunity.
Cytotoxic T lymphocytes specific for the simian immunodeficiency virus
Authors: Letvin Norman L , Schmitz Jörn E. , Jordan Holly L , Seth Aruna , Hirsch Vanessa M. , Reimann Keith A. , Kuroda Marcelo I.
Published: April 2006

Summary: A non‐human primate model for acquired immunodeficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)‐infected rhesus monkey, was used to explore the role of the AIDS virus‐specific cytotoxic T‐lymphocyce (CTL) response in disease pathogenesis. This CTL response was measured using the major histocompatibility complex (MHC) class I/peptide tetramer technology, large numbers of tetramer‐binding CDS’ T lymphocytes were demonstrable not only in the peripheral blood, but in lymph nodes and even in semen of chronically SIV‐infected monkeys. The central role of these effector T lymphocytes in containing SIV spread during primary infection was demonstrated by showing that early SIV clearance during primary infection correlated with the emergence of the tetramer binding CD8+ T lymphocytes and that in vivo depletion of CD8+ lymphocytes eliminated the ability of the infected monkeys to contain SIV replication. These observations suggest that an effective AIDS vaccine should elicit a potent virus‐specific CTL response. In fact, a live, recombinant SIV vaccine constructed using the attenuated pox virus vector modified vaccinia Ankara (MVA) elicited a high‐frequency CTL response, comparable in magnitude to that elicited by SIV infection itself This suggests that vaccine modalities such as MVA may prove useful in creating an effective human immunodeficiency virus (HIV) vaccine, These studies also indicate the power of both the SIV/macaque model and MHC class I/peptide tetramers for assessing AIDS vaccine strategies.
Therapeutic vaccines in HIV. 1 infection
Authors: Gotch Frances , Hardy Gareth , Imami Nesrina
Published: April 2006

Summary: In this review we address questions which must be considered if better attempts arc to be made to treat all persons presently infected with human immunodeficiency virus (HIV). There are thirty million people in the world presently living with HIV, only 10% of whom are likely to be able to access currently available drug therapy. Even when available, such therapy causes considerable inconvenience and undesirable clinical side effects, and fails to eradicate virus from a small reservoir of latently infected cells. Thus, we must ask what forms of alternative therapy might be used. One strategy that may he considered is to reduce virus levels as low as possible using highly active antiretroviral therapy (HAART), followed by modulation of host immunity with immunotherapy in order to effect an appropriate and efficient response mimicking that found in long‐term asymptomatic patients, with the aim of indefinitely maintaining the asymptomatic period following discontinuation of chemotherapy, or even of eradicating the virus from the latent reservoirs. In 1987, long before the advent of highly active antiretroviral therapy, J. Salk proposed the use of a ‘suitable potent non‐infectious (HIV) immunogen’ to delay or prevent the development of AIDS in infected individuals (1), The objective of administering such an agent was to ‘enhance and prolong the presetice of (immunologically) protective factors”. The stated aim at that time was ‘to destroy virus and viral antigen producing cells by the induction of the immune system's cytotoxic mechanisms known to rid the host of virus and virus producing cells”. Twelve years later, and after a quarter of a century living with HIV, and with the advent of HAART, is it time to use our knowledge of the host's own immune system to fight this seemingly intractable invader?
A rational basis for mucosal vaccination against HIV infection
Authors: Lehner Thomas , Bergmeier Lesley , Wang Yufei , Tao Louisa , Mitchell Elaine
Published: April 2006

Summary: The lack of success in the development of an effective conventional vaccine against HIV has focused attention on mucosal immunity. This is a rational move, since HIV is transmitted mostly by the mucosal route. The mucosal strategy is based on the concept that: a) HIV/SIV has to cross the mucosal‐regional lymph node‐blood barriers, each of which can prevent viral transmission or decrease the viral load, b) Immunization has to target directly the mucosal tissues or indirectly the regional lymph nodes, in order to prevent or control viral replication. This strategy is consistent with antigen localization and effective entry into the lymph nodes, driving the immune response, c) A dual immune mechanism may be necessary for effective mucosal protection, mediated by specific CD4 and CD8 T‐cell and antibody responses to the immunizing antigens, and innate antiviral factors and [i‐chemokines which downmodulate CCR5 co‐receptors. Targeted iliac lymph node immunization with SIVgp120 and p27 in alum prevents SIV infection or significantly decreases the viral load when challenged by the rectal route. Indeed, in addition to specific immunity, including significant sIgA antibody‐forming cells in the iliac lymph nodes, CD8‐suppressor factor and the three β‐chemokines (RANTES, macrophage inflammatory protein (MIP)‐ lα and MlP‐ 1β) are significantly associated with protection against rectal mucosal SIV infection.
Mucosal immunity and tolerance: relevance to vaccine development
Authors: Czerkinsky Cecil , Anjueie Fabienne , McGhee Jerry R. , Geoige‐Chundy Annie , Holmgren Jon , Kieny Marie‐Paule , Fujiyashi Kohlaro , Mestecky Jiri F. , Pierrefite‐Carle Valérie , Rusk Carok , Sun Jia‐Bin
Published: April 2006

Summary: The mucosal immune system of mammals consists of an integrated network of lymphoid cells which work in concert with innate host factors to promote host defense. Major mucosal effector immune mechanisms include secretory antibodies, largely of immunoglobulin A (IgA) isotype, cytotoxic T cells, as well as cytokines, chemokines and their receptors. Immunologic unresponsiveness (tolerance) is a key feature of the mucosal immune system, and deliberate vaccination or natural immunization by a mucosal route can effectively induce immune suppression. The diverse compartments located in the aerodigestive and genitourinary tracts and exocrine glands communicate via preferential homing of lymphocytes and antigen‐presenting cells. Mucosal administration of antigens may result in the concomitant expression of secretory immunoglobulin A (S‐IgA) antibody responses in various mucosal tissues and secretions, and under certain conditions, in the suppression of immune responses. Thus, developing formulations based on efficient delivery of selected anti‐gens/tolerogens, cytokines and adjuvants may impact on the design of future vaccines and of specific immunotherapeutic approaches against diseases associated with untoward immune responses, such as autoimmune disorders, allergic reactions, and tissue‐damaging inflammatory reactions triggered by persistent microorganisms.
Live attenuated Salmonella: a paradigm of mucosal vaccines
Authors: Sirard Jean‐Claude , Niedergang Florence , Kraehenbuhl Jean‐Pierre
Published: April 2006

Summary: Two key steps control immune responses in mucosal tissues: the sampling and transepkhelial transport of antigens, and their targeting into professional antigen‐presenting cells in mucosa‐associated lymphoid tissue. Live Salmonella bacteria use strategies that allow them to cross the epithelial barrier of the gut, to survive in antigen‐presenting cells where bacterial antigens are processed and presented to the immune cells, and to express adjuvant activity that prevents induction of oral tolerance. Two Salmonella serovars have been used as vaccines or vectors, S. typhimurium in mice and S. lyph'i in humans. S. lyphimurium causes gasiroenieritis in a broad host range, including humans, while S. typhi infection is restricted to humans. Attenuated S. typhitnurium has been used successfully in mice to induce systemic and mucosal responses against more than 60 heterolo‐gous antigens. Tbis review aims to revisit S. typhimurium‐based vaccination, as an alternative to S. typhi, with special emphasis on the molecttlar pathogenesis of S. typhimurium and the host response. We then discuss how such knowledge constitutes the basis for the rational design of novel live mucosal vaccines.
Polysaccharide vaccines as probes of antibody repertoires in man
Authors: Lucas Alexander H. , Reason Donald C.
Published: April 2006

Summary:Antibodies specific for capsular polysaccharide epitopes mediate immunity to encapsulated bacterial pathogens, and accordingly, vac‐cine development has focused upon the induction of these specificities. Efficacious vaccines, consisting of either polysaccharide alone or polysaccharide coupled to protein carriers, have been developed for a number of pathogens. Their clinical importance not with standing, these vaccines serve as model antigens to study the genetic and somatic forces molding adaptive immunity in man. In this article we review progress aimed at delineating the structure and dynamics of the human antibody repertoire to the Hoemophilus influenzoe type b poiysaccharide (Hib PS), a system which has been studied from infancy to old age. Collectively, the data reveal a repertoire which is encoded by a relatively iarge number of germline variable (V) region gene segments, but which is typically expressed within individuals as a markedly restricted, oligoclonal population. One particular V domain has attained canonical status because of its high penetrance at the population level and its predominance in individual repertoires, Although this combining site is assembled in early infancy and retains its prominence throughout life, its frequency of expression, affinity and protective function are dictated by the molecular form of the Hib PS immunogen (vaccine). The determinants of Hib PS binding affinity can include both germline and somatically‐acquired V region polymorphisms. We discuss how these properties of the Hib PS repertoire could impact immunity to Htb, and we consider the implications of these findings towards understanding die evolution of immunoglobulin germline V genes.
A role for cytokines in potentiation of malaria vaccines through immunological modulation of blood stage infection
Authors: Taylor‐Robinson Andrew W. , Smith Elizabeth C.
Published: April 2006

Summary: Malaria is the world's major parasitic disease, for which effective control measures are urgently needed. One of the difficulties hindering successful vaccine design against Plosmodium is an incomplete knowledge of antigens eliciting protective immunity, the precise types of immune response for which to aim, and how these can be induced. A greater appreciation of the mechanisms of protective immunity, on the one hand, and of immunopathology, on the other, should provide critical clues to how manipulation of the immune system may best be achieved. We are studying the regulation of the balance between T helper I (Th 1) and T helper 2 (Tb2) CD4+ T lymphocytes in immunity to asexual blood stages of malaria responsible for the pathogenicity of the disease. Protective immunity to the experimental murine malarias Plasmodium chabaudi and Plasmodium yoelii involves both Th1 and Tb2 cells, which provide protection by different mechanisms at different times of infection characterised by higher and lower parasite densities, respectively. This model therefore facilitates a clearer understanding of the Th1/Th2 equilibrium that appears central to immunoregulation of all host/pathogen relationships. It also permits a detailed dissection in vivo of the mechanisms of antimalarial immunity. Here, we discuss the present state of malaria vaccine development and our current research to understand the factors involved in the modulation of vaccine‐potentiated immunity.
Vaccination against helminth parasites ‐ the ultimate challenge for vaccinologists?
Authors: Maizels Rick M. , Holland Martin J. , Falcone Franco H. , Zang Xing‐Xing , Yazdanbakhsh Maria
Published: April 2006

Summary: Helminths are multicellular pathogens which infect vast numbers of human and animal hosts, causing widspread chronic disease and morbidity, Vaccination against these parasites requires more than identification of effective target antigens, because without understanding the immunology of the host–parasite relationship, ineffective immune mechanisms may he invoked, and there is a danger of amplifying immuno‐pathogenic responses. The fundamental features of the immune response to helminths are therefore summarised in the context of vaccines to helminths parasites. The contention between type‐1 and type‐2 responses is a central issue in helminth infections, which bias the immune system strongly to the type‐2 pathway. Evidence from both human and experimental animal infections indicates that both lineages contribute to immunity in differing circumstances, and that a balanced, response leads to the most favourable outcome. A diversity of immune mechanisms can be brought to bear on various helminth species, ranging from antibody‐independent macrophages, antibody‐dependent granulocyte killing, and non‐lymphoid actions, particularly in the gut. This diversity is highlighted by analysis of rodent infections, particularly in comparisons of cytokine‐depleted and gene‐targeted animals. This knowledge of protective mechanisms needs to he combined with a careful choice of parasite antigens for vaccines. Many existing candidates have been selected with host antibodies, rather than T‐cell responses, and include a preponderance of highly conserved proteins with similarities to mammalian or invertebrate antigens. Advantage has yet to he taken of parasite genome projects, or of directed searches for novel, parasite‐specific antigens and targets expressed only by infective stages and not mature forms which may generate immunopathology. With advances under way in parasite genomics and new vaccine delivery systems offering more rapid assessment and development, there are now excellent opportunities for new antihelminth vaccines.
Experimental approaches to the development of a recombinant hookworm vaccine
Authors: Hotez Peter J. , Ghosh Kashinath , Huwdon John , Narasimhan Sukanya , Jones Brion , Shuhua Xiao , Sen Liu , Bin Zhan , Haechou Xue , Hainan Ren , Heng Wang , Koski Raymond A.
Published: April 2006

Summary: Hookworm infection is a major parasitic cause of morbidity in the developing nations of the tropics. Development of a genetically engineered vaccine would be a useful tool in the control of this infection in highly endemic areas. Recombinant polypeptides belonging to the Ancylostoma secreted protein (ASP)‐1 family have shown promise for reducing hookworm burdens after larval challenge infections in mice. Typically, these polypeptides are expressed in Escherichia coli and administered as an alum precipitate. Vaccine protection is antibody dependent. It is anticipated that a cocktail of different recombinant hookworm antigens may be required in order to effectively prevent heavy hookworm infections and disease. The progress of this work has been hampered by the absence of both a convenient laboratory animal with which to study hookworm infections resembling human infection, as well as the lack of easy availability of native hookworm antigens. In addition, useful human serologic correlates of antihookworm immunity are still poorly defined.
Vaccines and passive immunological approaches for the control of fertility and hormone‐dependent cancers
Authors: Talwar C. P.
Published: April 2006

Summary: Reviewed here is the development of a vaccine against the human chorionic gonadotropin that prevents pregnancy in sexually active women without impairment of ovulation or derangement of menstrual regularity. Also reviewed are the vaccines inducing antibodies against the luteinizing hormone‐releasing hormone, which have immunotherapeutic potential in prostatic hypertrophy and other sex hormone‐dependent male and female cancers. The adoption of pasive immunization using humanized recombinant antihormone antibodies is advocated for assured efficacy and safe, prompt therapeutic action.
Generating MHC class I ligands from viral gene products
Authors: Yewdell Jonathan , Anton Luis C. , Bacik Igor , Schubert Ulrich , Snyder Heidi Link , Bennink Jack R.
Published: April 2006

Summary: MHC class I molecules function to present peptides comprised of eight to I 1 residues to CD8+ T lymphocytes. Here we review the efforts of our laboratory lo understand bow cells generate such peptides from viral gene products. We particularly focus on the nature of substrates acted on by cytosolic proteases, the contribution of proteasomes and nun‐proteasomal proteases lo peptide generation, the involvement of ubiquitination in peptide generation, the intracellular localization of proteasome generation of antigenic peptides, and the trimming of peptides in the endoplasmic reticulum.
Proteases involved in MHC dass II antigen presentation
Authors: Villadangos José A. , Bryant Rebecca A. R. , Deussing Jan , Driessen Christoph , Lennon‐Duménil Ana‐Maria , Riese Richard J. , Roth Wera , Saftig Paul , Shi Guo‐Ping , Chapman Harold A. , Peters Christoph , Ploegh Hidde L.
Published: April 2006

Summary: Major histocompatibility complex class II antigen presentation requires the participation of lysosomal proteases in two convergent processes. First, the antigens endocytosed by the antigen‐presenting cells must be broken down into antigenic peptides. Second, class II tnolecules are synthesized with their peptide‐binding site blocked by invariant chain (li), and they acquire the capacity to bind antigens only after Ii has been degraded in the compartments where peptides reside. The study of genetically modified tnice deficietit in single lysosomal proteases has allowed us to determine their role in these processes, Cathepsins (Cat) B and D. previously considered major players in MHC class II antigen presentation, are dispensable for degradation of Ii and for generation of several antigenic determinants. By contrast, Cat S plays an essential role in removal of Ii in B cells and dendritic cells, whereas Cat L apparently does so in thymic epithelial cells. Accordingly, the absence of Cat S and L have major consequences for the onset of humoral immtine responses and for T‐cell selection, respectively. It is likely that other as yet uncharacterized lysosomal enzymes also play a role in Ii degradation and in generation of antigenic determinants. Experiments involving drugs that interfere with protein traffic suggest that more than one mechanism for Ii removal, probably involving different proteases, can co‐exist in the same antigen‐presenting cell. These findings may allow the development of protease inhibitors with possible therapeutic applications.
The role of lysosomal proteinases in MHC class Il‐mediated antigen processing and presentation
Authors: Nakagawa Terry Y. , Rudensky Alexander Y.
Published: April 2006

Summary: The recent analysis of cathepsin‐deficient mice has shed light upon the role of lysosomal proteinases in the MHC class II processing and presentation pathway. Ubiquitous expression and involvement in the terminal degradation of proteins that intersect the endocytic pathway were previously perceived to be the hallmarks of these proteinases. However, recent evidence has demonstrated that several cathepsins are expressed in a tissue‐specific fashion and that partial proteolysis of specific biological targets is a key function of cathepsins in antigen processing. Our work has focused on the differential expression of the cysteine proteinases cathepsins L (CL) and S (CS) and its pertinence to the generation of MHC class II: peptide complexes. Analysis of CL‐deficient mice revealed a profound defect in invariant chain degradation in thymic cortical epithelial cells bur not in bone marrow‐derived antigen‐presenting cells (APCs) (B cells, dendritic cells, and macrophages), The tissue‐specific deficiency reflected the restricted pattern of expression of CL and CS in these cell types ‐ CL is expressed in thymic cortical epithelial cells but not in DC or B cells, while CS exhibits the opposite expression pattern. The differential expression of proteinases by distinct APCs may affect the types of peptides that are presented to T cells and thereby the immune responses that are ultimately generated.
Processing of bacterial antigens for peptide presentation on MHC class I molecules
Authors: Jo Wick Mary , Ljunggren Hans‐Gustaf
Published: April 2006

Summary: Professional antigen‐presenting cells (pAPC) can process and present exogenous antigens on major histocompatibility complex class 1 (MHC‐I) molecules. This unusual pathway for antigen presentation may represent a physiologically important step in the course of priming and tolerance induction of CD8+ T cells. In addition, it may play an important role in immunological surveillance for pathogens that survive in vacuolar compartments in APC. The goal of the present review is to discuss recent studies on the processing of bacterial‐derived antigens for presentation on MHC‐1 molecules. The antigen presentation emphasized will include bacteria that remain confined in vacuolar compartments. This is in contrast to antigens derived from bacteria that have intrinsic properties allowing translocation across membranes and access into the classical MHC‐I presentation pathway In particular, presentation of bacterial antigens by dendritic cells (DC) will be emphasized, and MHC‐I presentation of antigens derived from apoptotic cells, particularly cells induced to undergo apoptosis by microbial infection, will be presented. Finally, some special aspects of the interaction between bacteria and DC will be discussed as ii relates to DC maturation, antigen presentation and T‐cell stimulation.
Processing of Listeria monocytogenes antigens and the in vivo T‐cell response to bacterial infection
Authors: Busch Dirk H. , Kerksiek Kristen , Pamer Eric G.
Published: April 2006

Summary: Presentation of antigens to T lymphocytes is a critical step in the clearance of pathogens from their hosts and in the establishment of protective immunity. Several animal models have been developed to study this process, but few have been as informative as the murine immune response to Listerio monocytogenes infection. Herein we review the presentation of L, monocytogenes proteins by the MHC class I antigen‐processing pathway and the in vivo T‐cell response to these bacterial antigens. These studies demonstrate the following: I) The size of a peptide‐specific T‐cell response does not correlate with the amount of epitope presented by infected cells; 2) T cells specific for dominant epitopes do not, in the case of L. monocytogenes infection, inhibit responses to subdominant epitopes; 3) T cells responding to different epitopes presented by MHC class la molecules expand, contract and enter the memory pool synchronously; 4) Repeated in vivo expansion of antigen‐specific T‐cell populations results in a narrowing of their T‐cell receptor repertoire and in an increase in their affinity for antigen; and S) T cells restricted by H2‐M3 MHC class Ib molecules constitute a major part of the primary response to bacterial infection, but appear to play a relatively smaller role in memory responses. These studies have provided a novel glimpse of the relationship between antigen processing and in vivo T‐cell responses to infection, and provide a foundation for more detailed analyses of T‐cell‐mediated adaptive immunity.
Intracellular traffic to compartments for MHC class II peptide loading: signals for endosomal and polarized sorting
Authors: Bakke Oddmund , Nordeng Tommy W.
Published: April 2006

Summary: In this review we focus on the traffic of MHC class II and endocytosed antigens to intracellular compartments where antigenic pep‐tides are loaded. We also discuss briefly the nature of the peptide loading compartment and the sorting signals known to direct antigen receptors and MHC class II and associated molecules to this location, MHC dass II molecules are expressed on a variety of polarized epithelial and endothelial cells, and polarized cells are thus potentially important for antigen presentation. Here we review some cell biological aspects of polarized sorting of MHC class II and the associated invariant chain and the signals that are involved in the sorting process to the basolateral domain. The molecules involved in sorting and loading of peptide may modulate antigen presentation, and in particular we discuss how invariant chain may change the cellular phenotype and the kinetics of the endosomal pathway.
Intracellular transport and peptide loading of MHC class II molecules: regulation by chaperones and motors
Authors: Wubbolts Richard , Neefjes Jacques
Published: April 2006

Summary: MHC dass II molecules are important in the onset and modulation of cellular immune responses. Studies on the intracellular transport of these molecules has provided insight into the way pathogens are processed and presented at the cell surface and may result in future immunological intervention strategies. Recent reviews have extensively described structural properties and early events in the biosynthesis of MHC class II (1‐3). In this review, the focus will be on the function of the dedicated chaperone proteins Ii, DM and DO in the class II assembly, transport and peptide loading as well on proteins involved in transport steps late in the intracellular transport of MHC class II.
Mechanisms and consequences of peptide selection by the I‐Ak class II molecule
Authors: Latek Robert R. , Unanue Emil R.
Published: April 2006

Summary: Important quantitative parameters can be utilized to define the selection and the immunogenicity of protein antigens precisely at a biochemical and a cellijlar level. Here we describe a nacurally processed family of peptides comprising the dominant hen egg white lysozyme epitope, its major contribution to surface I‐Ak molecules, the primary and auxiliary peptide anchors involved in its selection, and its display of T‐cell receptor contacts. In addition, we explore the importance of the processing events that lead to the generation of residues flanking the minimal core epitope, the quantification of T‐cell responses directed toward the epitope, and the ability of the dominant epitope to form two unique conformations within the binding groove. Lastly, we address the relationship between this dominant and a minor lysozyme epitope.
Individual hydrogen bonds play a critical role in MHC class II:peptide interactions: implications for the dynamic aspects of class II trafficking and DM‐mediated peptide exchange
Authors: Sant Andrea J. , Beeson Craig , McFarland Benjamin , Cao Jun , Ceman Stephanie , Bryant Paula Wolf , Wu Shenhong
Published: April 2006

Summary: Determination of the crystal structure of class II:peptide complexes has shown that in addition to pocket interactions involving the side chains of the peptide, peptide binding to MHC class II molecules is characterized by a series of hydrogen bonds which are contributed by genetically conserved amino acid residues in the class II molecule to the main chain of the peptide. Our experiments have revealed an unexpectedly large contribution of hydrogen bonds at the periphery of the MHC peptide binding pocket to MHC class II function. Kinetic studies have shown that peptide dissociation rates are profoundly accelerated by loss of a single hydrogen bonding residue. The magnitude of the effects seen with the loss in potential for a single hydrogen bond support a co‐operative model in which individual bonds between class II and peptide are dependent on the integrity of neighboring interactions. Collectively our studies have revealed that MHC class II structure, peptide binding and intracellular trafficking events are critically dependent on the integrity of the hydrogen bonding network between class II molecules and its bound peptide.
Antigen presentation by parenchymal cells: a route to peripheral tolerance?
Authors: Murelii‐Berg Federica M. , Lechler Robert I.
Published: April 2006

Summary: T‐cell activation and the development of efficient immune responses requires the delivery, by the antigen‐presenting cell, of two distinct signals. The first results from the engagement of the TCR:CD3:CD4 complex, and the second from the interaction of CD28 with the B7 family of co‐stimulatory molecules. In this context, the physiological significance and the functional consequences of antigen presentation by B7‐deficient parenchymal cells, which express MHC class II molecules as a result of inflammation, remains a matter of debate. In this paper we have attempted to critically review the often conflicting reports on the functional effects of antigen presentation by epithelial and endothelial cells to T cells, both in vitro and in vivo, Our own findings are summarised in a model which Is consistent with the suggestion of an important role for antigen presentation by parenchymal cells in the induction and the maintenance of peripheral tolerance.
The intestinal epithelial cell: processing and presentation of antigen to the mucosal immune system
Authors: Campbell Nicola , Yio Xian Yang , So Lai Ping , Li Yin , Mayer Lloyd
Published: April 2006

Summary: The immunologic tone of the intestinal tract is one of suppressed or highly regulated responses. While there arc several components (intrinsic and extrinsic to the gut‐associated lymphoid tissue) responsible for this immunologically suppressed tone, the intestinal epithelial call (IEC) has been proposed as a key player in this process, IECs can take up and process antigen but distinct surface molecules and restriction elements allow them to present these antigens to unique regulatory T tells. These include the expression of the class II molecule CD I d as well as a novel CD8 ligand, gp180. These molecules come together to activate a subpopulation of CD8+ regulatory cells whose function is to suppress immune responses in an antigen non‐specific fashion most likely through cognate interactions. This form of regulation may be unique to the gut‐associated lymphoid tissue which is consistent with the unsual demands upon this part of the immune system.
HLA class II transgenic mice: models of the human CD4+ T‐cell immune response
Authors: Sønderstrup Grete , Cope Andrew P. , Patel Salil , Congia Mauro , Hain Norbert , Hall Frances C. , Parry Sarah L. , Fugger Lars H. , Michie Sara , McDevitt Hush O.
Published: April 2006

Summary: This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA‐DR4 transgenic lines with normally expressed HLA‐DR4 molecules have been produced. To obtain adequate positive selection of the HLA‐DR4‐restricted CD4+ T‐cell repertoire in these mice it is essential both to introduce a human CD4 transgene. and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA‐DR4 transgenic mice have been used to determine the immunogenic CD4+ T‐cell epitopes of several human autoantigenic proteins.
The chromosomal duplication model of the major histocompatibility complex
Authors: Kasahara Masanori
Published: April 2006

Summary: The major histocompatibility complex (MHC) is a genetic region that has been extensively studied by immunologists, molecular biologists, and evolutionary biologists. Nevertheless, our knowledge of how the MHC acquired its present‐day organization is quite limited. The recent discovery that the mammalian genome contains regions paralogous to the MHC has led us to the proposal that the MHC region of jawed vertebrates arose as a result of ancient chromosomal duplications. Here, I review the current status of this proposal.
The MHC Big Bang
Authors: Rached L. Abi , McDermott M. F. , Pontarotti P.
Published: April 2006

Summary: The human Major Histocompatibility Complex (MHC) shares similarities with three other chromosome regions in human. This could be the vestige of ancestral large scale duplications. We discuss here the possibility i) that these duplications occurred during two rounds of tetraploidization supposed to have taken place during chordate evolution before the jawed vertebrate radiation, and ii) that one of the quadruplicate regions, relaxed of functional constraints, gave rise to the vertebrate MHC by a quick round of gene cis‐duplication and cis‐exon shuffling. These different rounds of cis‐duplications and exon shufflings allowed the emergence of new genes participating in novel biological functions i.e. adaptive immune responses, Cis‐duplications and cis‐exon shufflings are ongoing processes in the evolution of some of these genes in this region as they have occurred and were fixed at different times and in different lineages during vertebrate evolution. In contrast, other genes within the MHC have remained stable since the emergence of jawed vertebrates.
Insight into the primordial MHC from studies in ectothermic vertebrates
Authors: Flajnik Martin , Ohta Yuko , Namikawa‐Yomada Chisato , Nonaka Masaru
Published: April 2006

Summary: MHC classical class I and class II genes have been identified in representative species from all major jawed vertebrate taxa, the oldest group being the cartilaginous fish, whereas no class I/II genes of any type have been detected in animals from older taxa. Among ectothermic vertebrate classes, studies of MHC architecture have been done in cartilaginous fish (sharks), bony fish (several teleost species), and amphibians (the frog Xenopus). The Xenopus MHC contains class I, class II, and class III genes, demonstrating that all of these genes were linked in the ancestor of the tetrapods, but the gene order is not the same as that in mouse/man. Studies of poly‐ploid Xenopus suggest that MHC genes can be differentially silenced when multiple copies are present; i.e. MHC 'subregions’can be silenced. Surprisingly, in all teleosts examined to date class I and class II genes are not linked. Likewise, class III genes like the complement genes factor B (Bf) and C4 are scattered throughout the genome of teleosts. However, the presumed classical class I genes are closely linked to the‘immune’proteasome genes, LMP2 and LMP7, and to the peptide‐transporter genes (TAP), implying that a true‘class I region’exists in this group. A similar type of linkage group is found in chickens and perhaps Xenopus, and thus it may reveal die ancestral organization of class I‐associated genes, In cartilaginous fish, classical and non‐classical class I genes have been isolated from three shark species, and class II A and B chain genes from nurse sharks. Studies of MHC linkage in sharks are being carried out to provide further understanding of the putative primordial organization of MHC. Segregation studies in one shark family point to linkage of class I and class II genes, suggesting that the non‐linkage of these genes in teleosts is a derived characteristic.
Conservation and diversification of MHC class I and its related molecules in vertebrates
Authors: Hashimoto Keiichiro , Okamura Kazuhiko , Yamaguchi Hisateru , Ototake Mitsuru , Nakanishi Teruyuki , Kurosaiva Yoshikazu
Published: April 2006

Summary: The elucidation of the complete peptide‐binding domains of the highly polymorphic shark MHC class I genes offered us an opportunity to examine the characteristics of their predicted protein products in the light of the latest advance m the structural studies of the MHC class I molecules. The results suggest that the fundamental characteristics in the T‐cell recognition of the MHC class I molecule/peptide complex are expected to have been established at the early stage of the vertebrate evolution. The elucidation of the typical classical class I molecules from fishes and also of some MHC class I‐related molecules may help us Co explore the common denominator of the ancient class I molecules.
The major histocompatibility complex in swine
Authors: Chardon Patrick , Renard Christine , Vaiman Marcel
Published: April 2006

Summary: In swine, the major histocompatibility complex (Mhc) or swine leukocyte antigen (SLA) is located on chromosome 7 and divided by the centromere. Thus, the telomeric class I and more centromeric class III regions are located on the p arm and the class II region is located on the q arm. The SLA region spans about 2 Mb, in which more than 70 genes have so far been characterized. Despite its division by the centromere, the spatial relationships between the genes in the class II and class III regions, and between the well‐conserved non‐class I genes of the class I region, are similar to those found in the human HLA complex. On the other hand, no orthologous relationships have been found between the Mhc class I genes in man and swine. In swine, the 12 SLA class I sequences constitute two distinct clusters. One chister comprises six classical class 1‐related sequences, while the other comprises five class I‐distantly related sequences including two swine homologous genes of the HLA Mhc class I chain‐related gene (MIC) sequence family. The number of functional SLA classical class I genes, as defined by serology, probably varies from one to four, depending on the haplotype. Some of the SLA class I‐distantly related sequences are clearly transcribed. As regards the SLA class II genes, some of them clearly code for at least one functional SLA‐DR and one SLA‐DQ heterodimer product, but none code for any DP product. The amino acid alignment of the variable domains of 33 SLA classical class I chains, and 62 DRβ and 20 DQβ chains confirmed the exceptionally polymorphic pattern of these polypeptides. Among the class II genes, the genes are either monomorphic, like the DRA gene, or oligomorphic, like the DQA genes. In contrast, the DRB and DQB genes display considerable polymorphism, which seems more marked in DRB than DQB genes.
Sequence organisation of the class II region of the human MHC
Authors: Beck Stephan , Trowsdale John
Published: April 2006

Summary: We present the genomic organisation of the extended class II region of the human MHC, This initial sequence, which is nearing completion, spans about 1.2 Mbp and is at present a composite of more than one haplotype. The sequencing of single haplotypes is planned for the future. The current sequence encompasses all of the known class II genes at the DP, DO, DM, DQ and DR loci as well as the transporter associated with antigen processing (TAP)/low molecular weight protein (LMP) antigen processing genes and the Tapasin locus, at the extended centromeric end.
γδ intraepithelial lymphocytes drive tumor necrosis factor‐α responsiveness to intestinal iron challenge: relevance to hemochromatosis
Authors: Ten Elshof Amy E. , Brittenham Gary M. , Chorney Karen A. , Page Michael J. , Gerhard Glenn , Cable Edward E. , Chorney Michael J.
Published: April 2006

Summary: The dependence of intestinal epithelial cell (IEC) growth and differentiation on intraepithelial lymphocytes (IELs) expressing the gamma/delta (γδ) T‐cell receptor (TCR), suggested a potential role for γδ+ IELs in the regulation of iron absorption. We therefore examined the levels of hepatic iron and the IEL cytokine responses in C57BL/6J control and class I and TCR knockout lines (placed on a C57BL/6J genetic background) following the administration of supplemental dietary iron. The highest level of liver iron was found in the β2‐microglobulin knockout (β2m‐/‐) mice followed by the TCR‐δ knockout (TCRδ‐/‐) animals. TCR‐α knockout (TCRα‐/‐) and control animals did not differ in their iron levels. Liver iron loading correlated inversely with rhe ability of the mice to generate an IEL tumor necrosis factor (TNE)‐α response. These observations suggest a model in which IEC iron loading is communicated to IELs via the HFE class I protein. The result of this communication is the initiation of TNE‐α release by γδ+ IELs (sustained by macrophages and dendritic cells) contributing to the upregulation of ferritin expression and possibly to the normal maintenance of the IEC apoptotic pathway.
Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease
Authors: Dawkins Roger , Leelayuwat Chanvit , Gaudieri Silvana , Tay Guan , Hui Jennie , Cattley Sonia , Martinez Patricia , Kulski Jerzy
Published: April 2006

Summary: The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with insertion and deletion (indels), In the alpha block surrounding HLA‐A, there are ten duplication units or beads on the 62,1 ancestral haplotype. Each bead contains or contained sequences representing Class 1, PERB11 (MHC Class I chain related (MIC)) and human endogenous retrovirus (HERV) 16, Here we consider explanations for co‐occurrence of genomic polymorphism, duplication and HERVs and we ask how these features encode susceptibility to numerous and very diverse diseases. Ancestral haplotypes differ in their copy number and indels in addition to their coding regions. Disease susceptibility could be a function of all of these differences. We propose a model of the evolution of the human MHC. Population‐specific integration of retroviral sequences could explain rapid diversification through duplication and differential disease susceptibility. If HERV sequences can be protective, there are exciting prospects for manipulation. In the mean‐while, it will be necessary to understand the function of MHC genes such as PEKB11 (MIC) and many others discovered by genomic sequencing.