bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Single Specific Amino Acid Residue in Peptide Antigens Is Sufficient to Activate Memory CTL: Potential Role of Cross-Reactive Peptides in Memory T Cell Maintenance
Authors: Reali Eva , Guerrini Remo , Marastoni Mauro , Tomatis Roberto , Grazia Masucci Maria , Traniello Serena , Gavioli Riccardo 
Published: December 2022

AbstractIn the present study, we examined the structural requirements of peptide Ags for productive interactions with the TCR of CTL. For this purpose, we used as a model a previously identified immunodominant epitope that represents the target of EBV-specific HLA-A11-restricted CTL responses. By the use of peptides having minimal sequence homology with the wild-type epitope, we demonstrated that it is possible to selectively expand and reactivate memory CTL precursors without triggering the lytic mechanisms of wild-type specific effectors. In fact, stimulation of PBL from EBV-seropositive donors by polyalanine analogues, sharing only the putative TCR contact residue with the natural epitope, exclusively induced clonal expansion and reactivation of EBV-specific memory CTL precursors. Interestingly, these polyalanine peptides failed to trigger the cytotoxic function of CTLs specific for the wild-type viral epitope. This clearly indicates that reactivation of memory CTL precursors and triggering of the cytotoxic function have different requirements. The same phenomenon was observed using as stimulators naturally occurring peptides carrying the appropriate TCR contact residue. These data strongly suggest that cross-reactive peptides may play an important role in the expansion and reactivation of CTL clones from the memory T cell pool, and may be involved in long-term maintenance of T cell memory.
EBV-Induced Expression and HLA-DR-Restricted Presentation by Human B Cells of αB-Crystallin, a Candidate Autoantigen in Multiple Sclerosis
Authors: van Sechel Arianne C. , Bajramovic̀ Jeffrey J. , van Stipdonk Marianne J. B. , Persoon-Deen Carla , Geutskens Sacha B. , van Noort Johannes M. 
Published: December 2022

Abstract
The development of multiple sclerosis is most likely influenced by autoimmune responses to central nervous system myelin proteins as well as by infections with common viruses such as EBV and human herpesvirus-6. However, much remains to be established on how these factors interact. In this study, we show that upon EBV infection, human B cells start to express αB-crystallin, a small stress protein that was identified previously as an immunodominant Ag of CNS myelin in multiple sclerosis patients. EBV-induced expression of αB-crystallin in B cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory αB-crystallin-specific Th cells. While αB-crystallin is present in EBV-infected human B cells, the protein is absent from human lymphoid tissues under normal conditions. This is in sharp contrast to other stress proteins such as heat-shock protein (hsp)27 and hsp60 that are ubiquitously expressed in these tissues. In addition, the absence of αB-crystallin from lymphoid tissues in humans is unique as compared with other mammals. All other species examined, including rodents, sheep, and primates, showed constitutive expression of αB-crystallin in secondary lymphoid tissues and sometimes even in the thymus. Since constitutive lymphoid expression most likely results in immunologic tolerance, such a state of tolerance to αB-crystallin can be expected for all of these species, but not for humans. When taken together, our data provide evidence for a novel mechanism by which common viral infections can trigger myelin-directed autoimmunity in a way that is unique for humans.
Generation of Tumor Immunity by Bone Marrow-Derived Dendritic Cells Correlates with Dendritic Cell Maturation Stage
Authors: Labeur Marta S. , Roters Berthold , Pers Birgit , Mehling Annette , Luger Thomas A. , Schwarz Thomas , Grabbe Stephan 
Published: December 2022

AbstractBone marrow-derived dendritic cells (BmDC) are potent APC and can promote antitumor immunity in mice when pulsed with tumor Ag. This study aimed to define the culture conditions and maturation stages of BmDC that enable them to optimally function as APC in vivo. BmDC cultured under various conditions (granulocyte-macrophage CSF (GM-CSF) or GM-CSF plus IL-4 alone or in combination with Flt3 ligand, TNF-α, LPS, or CD40 ligand (CD40L)) were analyzed morphologically, phenotypically, and functionally and were tested for their ability to promote prophylactic and/or therapeutic antitumor immunity. Each of the culture conditions generated typical BmDC. Whereas cells cultured in GM-CSF alone were functionally immature, cells incubated with CD40L or LPS were mature BmDC, as evident by morphology, capacity to internalize Ag, migration into regional lymph nodes, IL-12 secretion, and alloantigen or peptide Ag presentation in vitro. The remaining cultures exhibited intermediate dendritic cell maturation. The in vivo Ag-presenting capacity of BmDC was compared with respect to induction of both protective tumor immunity and immunotherapy of established tumors, using the poorly immunogenic squamous cell carcinoma, KLN205. In correspondence to their maturation stage, BmDC cultured in the presence of CD40L exhibited the most potent immunostimulatory effects. In general, although not entirely, the capacity of BmDC to induce an antitumor immune response in vivo correlated to their degree of maturation. The present data support the clinical use of mature, rather than immature, tumor Ag-pulsed dendritic cells as cancer vaccines and identifies CD40L as a potent stimulus to enhance their in vivo Ag-presenting capacity.
A Theiler’s Virus Alternatively Initiated Protein Inhibits the Generation of H-2K-Restricted Virus-Specific Cytotoxicity
Authors: Lin Xiaoqi , Roos Raymond P. , Pease Larry R. , Wettstein Peter , Rodriguez Moses 
Published: December 2022

AbstractIn susceptible mouse strains, the wild-type Daniel’s (wt-DA) strain of Theiler’s murine encephalomyelitis virus induces a persistent central nervous system (CNS) infection with chronic demyelination. The virus is cleared from resistant mice with no resulting demyelination. We characterized the role of the DA L* protein in late demyelination and persistent infection. The DA genome has two alternative reading frames, encoding the virus polyprotein and L*, respectively. The mutant virus DAL*-1 fails to synthesize L* and does not persist in the CNS of wt-DA-susceptible SJL/J or B10.S mice. Since class I-restricted cytotoxicity has been shown to determine resistance to virus persistence and demyelination in this model, virus-specific cytotoxicity in the CNS of DA-resistant (B6 or B10) and -susceptible (SJL/J and B10.S) mice during the acute stage of DA and DAL*-1 infection was characterized. Following intracerebral inoculation with DAL*-1, virus-specific Db- and Kb-restricted CTLs were demonstrated in the CNS of resistant B10 mice, whereas only Db-restricted CTL were found in wt-DA-inoculated mice. CTLs specific to wt-DA or DAL*-1 recognized class I-presented peptides from either of the viruses. Of particular interest, Ks-restricted virus-specific cytotoxicity-restricted CTLs were identified in the CNS of susceptible SJL/J (H-2s) and B10.S (H-2s) mice inoculated with DAL*-1. In contrast, no virus-specific CTLs were identified in the CNS of SJL/J and B10.S mice inoculated with wt-DA. We propose that L* inhibits the generation of H-2K-restricted virus-specific cytotoxicity in the CNS, permitting a persistent infection in susceptible strains, with subsequent inflammatory demyelination in the CNS similar to that in human multiple sclerosis.
CC-Chemokine Receptor 6 Is Expressed on Diverse Memory Subsets of T Cells and Determines Responsiveness to Macrophage Inflammatory Protein 3α
Authors: Liao Fang , Rabin Ronald L. , Smith Craig S. , Sharma Geetika , Nutman Thomas B. , Farber Joshua M. 
Published: December 2022

AbstractCC-chemokine receptor (CCR) 6 is the only known receptor for macrophage inflammatory protein (MIP)-3α, a CC chemokine chemotactic for lymphocytes and dendritic cells. Using anti-serum that we raised against the N-terminal residues of CCR6, we have characterized the surface expression of CCR6 on peripheral blood leukocytes and we have correlated CCR6 expression with responses to MIP-3α. We found that CCR6 was expressed only on memory T cells, including most α4β7 memory cells and cutaneous lymphocyte-associated Ag-expressing cells, and on B cells. Accordingly, chemotaxis of T cells to MIP-3α was limited to memory cells. Moreover, calcium signals on T cells in response to MIP-3α were confined to CCR6-expressing cells, consistent with CCR6 being the only MIP-3α receptor on peripheral blood T cells. Unlike many CC chemokines, MIP-3α produced a calcium signal on freshly isolated T cells, and CCR6 expression was not increased by up to 5 days of treatment with IL-2 or by cross-linking CD3. Despite their surface expression of CCR6, freshly isolated B cells did not respond to MIP-3α. In addition to staining peripheral blood leukocytes, our anti-serum detected CCR6 on CD34+ bone marrow cell-derived dendritic cells. Our data are the first to analyze surface expression of CCR6, demonstrating receptor expression on differentiated, resting memory T cells, indicating differences in receptor signaling on T cells and B cells and suggesting that CCR6 and MIP-3α may play a role in the physiology of resting memory T cells and in the interactions of memory T cells, B cells, and dendritic cells.
Presence or Absence of TGF-β Determines IL-4-Induced Generation of Type 1 or Type 2 CD8 T Cell Subsets
Authors: Erard Francois , Garcia-Sanz Jose A. , Moriggl Richard , Wild Marie-Therese 
Published: December 2022

AbstractCD8+ T cells often differentiate into highly cytotoxic cells, secreting a Th1-like or type 1 cytokine pattern characterized by the production of IFN-γ. However, cytotoxic, and in some reports, noncytotoxic, type 2 cells that secrete IL-4, IL-5, or IL-10 instead of IFN-γ, can be generated when CD8+ T cells are primed in the presence of IL-4. Here, we show that IL-4 can also generate typical CD8 type 1 responses. Indeed, while presence of TGF-β biases the development of CD8 T cells that, then, produce little cytolytic activity and IFN-γ, addition of IL-4 results in the recovery of cytotoxicity and IFN-γ production. The cooperative effects of TGF-β and IL-4 imply dual functions, not only for IL-4, but also for TGF-β. Indeed, depending on the presence or absence of IL-4, TGF-β either inhibits or induces the generation of type 1 CD8+ T cells. Physiologically, the ratio of local IL-4/TGF-β concentration may therefore be a critical element in determining the outcome of T cell responses to pathogen and autoantigens. It allows CD8 T cells to switch from an immunotolerant state in the presence of only TGF-β or IL-4, to an immunocompetent proinflammatory type 1 state in the absence or presence of both cytokines.
TCR Activation Inhibits Chemotaxis Toward Stromal Cell-Derived Factor-1: Evidence for Reciprocal Regulation Between CXCR4 and the TCR
Authors: Peacock James W. , Jirik Frank R. 
Published: December 2022

AbstractStromal cell-derived factor-1 (SDF-1), a C-X-C family chemokine, is a potent T lymphocyte chemoattractant. We investigated the effects of T cell activation on the chemotactic response to SDF-1. Anti-CD3 Ab stimulation of either Jurkat T cells or murine peripheral CD4+ T lymphocytes produced a dramatic inhibition of SDF-1-induced chemotaxis. In contrast, the SDF-1 responses of Jurkat clones with deficiencies in key TCR signaling components (Lck, CD45, and TCR-β), were only marginally reduced by anti-CD3 stimulation. Similar to PMA treatment, which abolished both CXCR4 receptor expression and the chemotactic response of Jurkat cells to SDF-1, anti-CD3 Ab treatment reduced cell surface expression of CXCR4 to 65% of the control value, an effect that was blocked by protein kinase C inhibitors. Our data suggest that initial T cell activation events inhibit the response of Jurkat T cells to CXCR4 stimulation. In contrast, SDF-1 treatment resulted in a reduction of tyrosine phosphorylation of the TCR downstream effectors, ZAP-70, SLP-76, and LAT (linker for activation of T cells), suggesting that this chemokine potentially regulates the threshold for T cell activation.
The First Dose of aHaemophilus influenzaeType b Conjugate Vaccine Reactivates Memory B Cells: Evidence for Extensive Clonal Selection, Intraclonal Affinity Maturation, and Multiple Isotype Switches to IgA2
Authors: Hougs Lotte , Juul Lars , Ditzel Henrik J. , Heilmann Carsten , Svejgaard Arne , Barington Torben 
Published: December 2022

AbstractThe Ab response of a healthy adult to the first dose of a Haemophilus influenzae type b capsular polysaccharide (HibCP) conjugate vaccine was studied at the level of Ig gene usage by circulating Ab-secreting cells. Forty-one IgA and 17 IgG mRNA sequences were obtained. The major part of the response was confined to IgA Ab-secreting cells, and 72% of the IgA sequences were derived from the progeny of a single rearranged B cell. These sequences could be arranged in a genealogical tree showing multiple somatic mutations and at least two intraclonal isotype switches to IgA2. Fourteen somatic mutations were shared by this clonal progeny, indicating that extreme clonal selection had occurred early in the clonal development. Taking into account the frequency of somatic mutations and the clone size, it was evident that the responding cell population must have originated from a mutated, highly selected, and expanded population of cells existing before vaccination, i.e., memory B cells. The dominating heavy and light chains of the response were combined in a Fab that bound HibCP. It was shown that the shared heavy and light chain mutations increased the affinity for HibCP considerably, indicating that the clonal selection had been driven by affinity. Pre-existing memory cells in unvaccinated adults may explain several features of Ab responses to polysaccharide vaccines and may play a role in acquiring the ability to respond to pure polysaccharides during infancy.
Differential Effects of Type I IFNs on the Growth of WC1− CD8+ γδ T Cells and WC1+ CD8− γδ T Cells In Vitro
Authors: Tuo Wenbin , Bazer Fuller W. , Davis William C. , Zhu Daming , Brown Wendy C. 
Published: December 2022

AbstractType I IFNs have a broad array of immunoregulatory functions that include up-regulation of type 1 immune responses through enhancing differentiation and activation of CD8+ T cells and CD4+ Th1 cells. Ovine trophoblast IFN-τ is a recently described type I IFN with the potential for therapeutic use, based on its potent antiviral activity yet low toxicity. Studies were designed to determine the immunoregulatory effects of IFN-τ on Ag-stimulated T cells, and a novel effect of type I IFNs on γδ T cells was observed. In cultures of parasite Ag-stimulated bovine T cells that contained a mixture of αβ and γδ T cells, both IFN-τ and IFN-α suppressed the expansion of WC1+ CD2− CD6− CD8− γδ T cells, yet stimulated the growth of WC1− CD2+ CD6+ CD8+ γδ T cells and CD8+ αβ T cells. The CD8+ γδ T cell subset expressed high levels of the IL-2R α-chain. Furthermore, we showed that type I IFN enhanced IL-2 production by these Ag-stimulated T cell lines. In short term cultures of PBMC, IL-2 stimulated an expansion of WC1− CD6+ CD8+ γδ T cells, which was significantly increased by IFN-τ, even though IFN-τ alone did not support cell survival. These studies demonstrate for the first time that type I IFNs differentially modulate the proliferation of different subsets of γδ T cells, which appears to act in part via IL-2.
Intranasal Immunization with Plasmid DNA-Lipid Complexes Elicits Mucosal Immunity in the Female Genital and Rectal Tracts
Authors: Klavinskis Linda S. , Barnfield Christina , Gao Liquan , Parker Suezanne 
Published: December 2022

AbstractThe development of vaccines against pathogens transmitted across the genito-rectal mucosa that effectively stimulate both secretory IgA Abs and cytotoxic T lymphocytes in the genital tract and CTL in the draining lymph nodes (LN) has proven a major challenge. Here we report a novel, noninvasive approach of genetic vaccination via the intranasal route. Such vaccination elicits immune responses in the genital and rectal mucosa, draining LNs, and central lymphoid system. Intranasal immunization with plasmid DNA-lipid complexes encoding the model Ag firefly luciferase resulted in dissemination of the DNA and the encoded transcript throughout the respiratory and gastrointestinal tracts, draining LNs, and spleen. Complexing the plasmid DNA with the lipid DMRIE/DOPE enhanced expression of the encoded protein in the respiratory tract, increased specific secretory IgA Ab in the vaginal and rectal tracts, and increased the circulating levels of specific IgA and IgG. In addition, intranasal DNA immunization resulted in generation of Ag-specific CTL that were localized in the genital and cervical LNs and spleen. These results suggest that intranasal immunization with plasmid DNA-lipid complexes may represent a generic immunization strategy against pathogens transmitted across the genito-rectal and other mucosal surfaces.
High Level Expression of the Xlr Nuclear Protein in Immature Thymocytes and Colocalization with the Matrix-Associated Region-Binding SATB1 Protein
Authors: Escalier Denise , Allenet Bénédicte , Badrichani Anne , Garchon Henri-Jean 
Published: December 2022

AbstractThe X-linked lymphocyte-regulated (Xlr) protein is a 30,000 Mr nuclear protein bearing homology with meiosis-specific proteins and expressed in late stage B lymphoid cell lines. In the present study we investigated its expression in the T lymphoid lineage. In adults, a high level of expression was detected in CD4−CD8− thymocytes. Most remarkably, the peak of Xlr expression occurred early during thymus cell ontogeny, precisely on days 14–15 of gestation, and was associated with the first wave of pre-T cell differentiation. Its onset preceded the rearrangement of TCR genes, as Xlr expression was conserved in thymus cells from RAG10/0 mice. The lower expression of Xlr on day 13 of fetal development, the bright Thy1+ phenotype of Xlr-positive cells, their large size, and their absence from subcapsular areas suggest that Xlr expression must be turned on within the thymus and not in prethymic precursors. From day 16 of gestation, Xlr expression decreased markedly. At birth and later, Xlrhigh cells were mostly large cells scattered throughout the cortical area. As shown by confocal microscopy, expression of Xlr closely overlapped that of SATB1, which binds special AT-rich DNA sequences associated with the nuclear matrix and plays an important regulatory role for many genes. The remarkably regulated expression of Xlr in the lymphoid cell lineage and of its homologue Xmr in the germ cell lineage suggests that they might play an important role in chromatin metabolism at critical stages of differentiation during which the genome undergoes irreversible rearrangements.
Specific Recognition of HLA-E, But Not Classical, HLA Class I Molecules by Soluble CD94/NKG2A and NK Cells
Authors: Brooks Andrew G. , Borrego Francisco , Posch Phillip E. , Patamawenu Apisit , Scorzelli Christopher J. , Ulbrecht Matthias , Weiss Elizabeth H. , Coligan John E. 
Published: December 2022

AbstractThe CD94/NKG2 receptors expressed by subpopulations of NK cells and T cells have been implicated as receptors for a broad range of both classical and nonclassical HLA class I molecules. To examine the ligand specificity of CD94/NKG2 proteins, a soluble heterodimeric form of the receptor was produced and used in direct binding studies with cells expressing defined HLA class I/peptide complexes. We confirm that CD94/NKG2A specifically interacts with HLA-E and demonstrate that this interaction is dependent on the association of HLA-E with peptide. Moreover, no interaction between CD94/NKG2A and classical HLA class I molecules was observed, as assayed by direct binding of the soluble receptor or by functional assays using CD94/NKG2A+ NK cells. The role of the peptide associated with HLA-E in the interaction between HLA-E and CD94/NKG2A was also assessed. All class I leader sequence peptides tested bound to HLA-E and were recognized by CD94/NKG2A. However, amino acid variations in class I leader sequences affected the stability of HLA-E. Additionally, not all HLA-E/peptide complexes examined were recognized by CD94/NKG2A. Thus CD94/NKG2A recognition of HLA-E is controlled by peptide at two levels; first, peptide must stabilize HLA-E and promote cell surface expression, and second, the HLA-E/peptide complex must form the ligand for CD94/NKG2A.
A NF-κB/c-myc-Dependent Survival Pathway Is Targeted by Corticosteroids in Immature Thymocytes
Authors: Wang Weihong , Wykrzykowska Joanna , Johnson Todd , Sen Ranjan , Sen Jyoti 
Published: December 2022

AbstractGlucocorticoid hormones modulate T cell maturation in vivo. While low levels of hormones are required for appropriate T cell development, high levels of glucocorticoid hormones target immature developing thymocytes for cell death during systemic stress. In this report, we propose a molecular mechanism for the induction of apoptosis in CD4+CD8+ double-positive thymocytes by dexamethasone in vivo. Dexamethasone injection induced the expression of IκBα and IκBβ in thymocytes and down-regulated NF-κB DNA binding activated by intrathymic signals. Down-regulation of NF-κB DNA binding preceded cell death, suggesting that NF-κB may be important for the survival of immature thymocytes. In addition, ex vivo treatment of thymocyte single-cell suspension with dexamethasone accelerated p65/RelA down-regulation and cell death. Conversely, NF-κB induction diminished dexamethasone-induced death. Expression of the c-myc proto-oncogene, a NF-κB target, was also reduced in thymocytes of dexamethasone-treated animals, and ectopic transgenic expression of c-myc in mice provided partial rescue of double-positive thymocytes from dexamethasone mediated cell death. These observations suggest that viability of CD4+CD8+ thymocytes may be maintained by an NF-κB/c-myc-dependent pathway in vivo.
Optimal Vaccination AgainstSchistosoma mansoniRequires the Induction of Both B Cell- and IFN-γ-Dependent Effector Mechanisms
Authors: Jankovic Dragana , Wynn Thomas A. , Kullberg Marika C. , Hieny Sara , Caspar Patricia , James Stephanie , Cheever Allen W. , Sher Alan 
Published: December 2022

AbstractMice immunized with radiation-attenuated cercariae of Schistosoma mansoni display resistance to challenge infection, which increases with multiple boosting. Protection in animals receiving a single vaccination is thought to involve a primarily cell-mediated, IFN-γ-dependent mechanism, while humoral immunity has been shown to contribute to challenge rejection in multiply (three times) immunized mice. To better understand the respective contribution of the B lymphocyte- and IFN-γ-dependent effector arms in host resistance, we compared vaccine-induced immunity in B cell-deficient (μMT) and IFN-γ knockout (GKO) animals. Unexpectedly, after a single vaccination, B cell knockout (KO) mice displayed reduced protection against challenge infection, although they developed a normal IFN-γ-dominated cytokine response. This defect in resistance was equivalent to that displayed by GKO animals. Moreover, whereas two additional vaccinations significantly increased the level of immunity in wild-type mice, the protection in B cell KO animals remained unchanged. In contrast, multiple vaccination resulted in increased but, nevertheless, defective resistance in GKO mice. Since FcR γ KO mice, which lack functional FcγRI, FcγRIII, and FcεRI, show no defects in vaccine-induced resistance after immunization either one or three times, the B cell-dependent mechanism of protection involved does not appear to require FcR signaling. Together, these findings indicate that effective vaccination against schistosomes depends on the simultaneous induction of both humoral and cell-mediated immunity, a conclusion that may explain the limited success of most subunit vaccine protocols designed to preferentially induce either B cell- or IFN-γ-dependent protective mechanisms.