bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice.
Authors: Christianson S W , Greiner D L , Hesselton R A , Leif J H , Wagar E J , Schweitzer I B , Rajan T V , Gott B , Roopenian D C , Shultz L D 
Published: December 2022

Abstract
Genetic crosses produced NOD/LtSz mice doubly homozygous for the severe combined immunodeficiency (scid) mutation and the beta2m (B2m) null allele. Both NOD/LtSz-scid/scid and NOD/LtSz-scid/scid B2m(null) mice lacked mature lymphocytes and serum Ig. However, homozygosity for the B2m(null) allele also resulted in the absence of MHC class I expression, loss of NK cell activity, accumulation of iron in the liver, and rapid clearance of human IgG1. NOD/LtSz-scid/scid B2m(null) mice supported markedly elevated levels of human T cell engraftment, compared with NOD/LtSz-scid/scid control animals, following injection with human PBMC. The increased engraftment was associated with a major increase in the number of human CD4+ T cells. Following injection with 20 million human PBMC, levels of human CD4+ T cells in the peripheral blood and spleen of NOD/ LtSz-scid/scid B2m(null) mice were 6- to 7-fold higher than those in NOD/LtSz-scid/scid mice and &gt;50-fold higher than those in C.B-17-scid/scid mice. The resulting normalization of CD4+/CD8+ ratios in NOD/LtSz-scid/scid B2m(null) mice is in sharp contrast to that observed in NOD/LtSz-scid/scid mice or in C.B-17-scid/scid mice. Circulating human IgG was cleared 6-fold more rapidly in NOD/LtSz-scid/scid B2m(null) mice than in NOD/LtSz-scid/scid mice. This rapid IgG clearance suggested a failure of the engrafted human lymphoid cells to maintain high circulating levels of human IgG. The higher levels of human CD4+ T cells and the normalization of the CD4:CD8 ratio that are observed in human PBMC-engrafted NOD/LtSz-scid/scid B2m(null) mice suggest that this system may be an excellent model for studies of HIV pathogenesis.
A tumor-associated and self antigen peptide presented by dendritic cells may induce T cell anergy in vivo, but IL-12 can prevent or revert the anergic state.
Authors: Grohmann U , Bianchi R , Ayroldi E , Belladonna M L , Surace D , Fioretti M C , Puccetti P 
Published: December 2022

Abstract
Ag-specific CD8+ cell responses, including delayed-type hypersensitivity in vivo and IFN-gamma production in vitro, are initiated by host immunization with P815AB, a self peptide bearing CTL epitopes and expressed by murine mastocytoma cells. Using P815AB-pulsed dendritic cells (DC) and monitoring class I-restricted skin test reactivity in DC-primed mice, we have previously shown that the development of a Th1-like response to P815AB requires T helper effects, such as those mediated by coimmunization with class II-restricted (helper) peptides or by the use of rIL-12. The adjuvanticity of IL-12 was suggested to involve improved recognition of class II-restricted epitopes of P815AB. In the present study, we provide evidence for the occurrence of I-A(d)-restricted epitopes in the tumor peptide. We also show that in the absence of helper peptide or rIL-12, P81 5AB not only failed to initiate CD8+ cell responses in vivo and in vitro, but resulted in a transient state of functional unresponsiveness, characterized by a profound inability of CD4+ cells to produce IL-2 in vitro. Ag-specific T cell anergy was also observed after neutralization of endogenous IL-12 at the time of priming with P815AB plus helper peptide. All of these effects were reversed by rIL-12, which was added to DC cultures and administered to the DC-recipient mice. Anergy induction may thus contribute to P81 5AB unresponsiveness in vivo. IL-12 may act to prevent or revert anergy to this tumor-associated and self peptide.
Molecular characterization and role in T cell activation of staphylococcal enterotoxin A binding to the HLA-DR alpha-chain.
Authors: Thibodeau J , Dohlsten M , Cloutier I , Lavoie P M , Bjork P , Michel F , Léveillé C , Mourad W , Kalland T , Sékaly R P 
Published: December 2022

Abstract
Superantigens bind to MHC class II-positive cells and stimulate T lymphocytes expressing specific V beta regions of the TCR. Two distinct regions of staphylococcal enterotoxin A superantigen (SEA) have been shown to affect the binding to MHC class II molecules. Results presented here demonstrate for the first time that the SEA-DR interaction can be affected by mutations on the class II alpha-chain. Furthermore, we have precisely mapped the interaction of the SEA N-terminal domain with the alpha1 domain of HLA-DR. Scatchard analysis using DAP cells transfected with mutant class II molecules showed a role for residue DR alpha K39 in the binding of SEA. Also, complementation experiments using mutant SEA molecules revealed an interaction between SEA residue F47 and position alphaQ18 on an outer loop of HLA-DR. These interactions between SEAF47 and the DR alpha-chain are critical, as they allow the recognition by an otherwise nonreactive V beta1+ T cell hybridoma and induction of tyrosine phosphorylation through the TCR.
Complement-inhibiting peptides identified by proximity to indels in the C3/4/5 protein family.
Authors: Ogata R T , Low P J 
Published: December 2022

Abstract
To find protein-protein interactive sites in complement component C3, we examined regions of C3 that are proximal to sites of length polymorphism or indels in the C345 protein family. We reasoned that indels probably mark protein interactive sites because they usually involve residues at protein surfaces. To test for the involvement of individual indels, we examined the effects on complement function of synthetic peptides corresponding to indel-proximal segments of C3. We inferred that if such a segment made direct contact with a C3 binding protein, then the corresponding peptide might also bind to that protein and inhibit binding to C3. Twenty-one peptides were tested; four of these inhibited complement-mediated erythrocyte lysis at &lt; or =100 microM and complement-mediated killing of Escherichia coli at about threefold higher levels. These results indicate that the four peptides act as specific inhibitors of complement. They also suggest that indels can be effective guides for locating interactive sites in C3 and in any protein that is a member of a protein family. Because only a linear sequence is required, a focus on indels may be particularly useful for identifying interactive sites in proteins for which a three-dimensional structure is unavailable.
Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients.
Authors: Remold-O'Donnell E , Cooley J , Shcherbina A , Hagemann T L , Kwan S P , Kenney D M , Rosen F S 
Published: December 2022

Abstract
The Wiskott-Aldrich syndrome (WAS) arises from defects of the X-chromosome gene WASP. Severe platelet defects, thrombocytopenia with small platelets, are a hallmark of the disease, but clinical immunodeficiency based in lymphocyte dysfunction varies from negligible to life threatening among WAS patients. To address the connection between WASP mutations and clinical outcomes, we generated and characterized a panel of patient B cell lines. Three cell lines from patients with exon 2 missense mutations and mild immune dysfunction were found to express substantial levels of WASP mRNA and protein. On the other hand, 8 of 10 cell lines from patients with moderate or severe immune dysfunction lack detectable WASP protein. The findings suggest that the clinical variability of the WAS can partially be explained by the level of WASP protein in the patient's cells.
Engagement of the signaling lymphocytic activation molecule (SLAM) on activated T cells results in IL-2-independent, cyclosporin A-sensitive T cell proliferation and IFN-gamma production.
Authors: Aversa G , Chang C C , Carballido J M , Cocks B G , de Vries J E 
Published: December 2022

Abstract
The expression and function of the novel signaling lymphocytic activation molecule (SLAM) are described. SLAM is present on immature thymocytes, CD45R0(high) memory T cells, T cell clones, CD56+ T cells, EBV-transformed B-cell lines and on a proportion of B cells. SLAM is rapidly induced on naive T cells, TCR gammadelta+ T cells, and B cells following activation. Engagement of SLAM by the agonistic anti-SLAM mAb A12 resulted in proliferation of T cell clones and Ag- or PHA-activated peripheral blood T cells. mAb A12-induced T cell proliferation is independent of IL-2 and sensitive to inhibition by cyclosporin A. The extent of the anti-SLAM-induced proliferation was related to the activation state of the T cells, since fully rested T cell clones failed to proliferate in response to mAb A12 stimulation, despite unchanged SLAM expression on their surface. Ligation of SLAM on activated peripheral T cells or T cell clones by mAb A12 induced IFN-gamma production in the absence of other exogenous stimuli, even in allergen-specific Th2 clones. These data indicate that stimulation via SLAM reverses the cytokine production profile of Th2 clones to a Th0 phenotype, whereas it further polarizes cytokine production by Th1 clones. Thus, SLAM is a novel receptor that mediates IL-2-independent expansion of activated T cells during immune responses, while concomitantly directing these proliferating cells to a Th0/Th1 pathway.
Synergistic induction of CTLA-4 expression by costimulation with TCR plus CD28 signals mediated by increased transcription and messenger ribonucleic acid stability.
Authors: Finn P W , He H , Wang Y , Wang Z , Guan G , Listman J , Perkins D L 
Published: December 2022

Abstract
T cell activation requires at least two signals transduced by the Ag-specific TCR plus a costimulatory receptor. The CD28 costimulatory molecule has been shown to promote T cell proliferation and cytokine production. CTLA-4, a cell surface molecule homologous to CD28, can function as a repressor of T cell activation. Thus, CTLA-4 and CD28 may have opposing functions during T cell activation. CTLA-4 is expressed at low levels on resting T cells and up-regulated after T cell activation. Regulation of CTLA-4 expression is critical to the normal regulation of immunity. For example, CTLA-4-deficient mice develop early onset lethal autoimmunity. We previously showed that CTLA-4 transcription is increased after T cell activation and that induction was controlled by 335 bp of CTLA-4 upstream sequence. In this work, we show that cell surface CTLA-4 expression is increased synergistically by TCR plus CD28 signals. Synergistic induction is mediated by two mechanisms: an enhanced rate of transcription and increased mRNA stability. In contrast to the regulation of IL-2 and IL-2R expression, which is inhibited by cyclosporin A-, but not rapamycin-dependent signal transduction pathways, CTLA-4 expression is inhibited by either cyclosporin A or rapamycin. Thus, synergistic induction of CTLA-4 expression requires both cyclosporin A- and rapamycin-dependent signals.
Differential CC chemokine-induced enhancement of T helper cell cytokine production.
Authors: Karpus W J , Lukacs N W , Kennedy K J , Smith W S , Hurst S D , Barrett T A 
Published: December 2022

Abstract
Chemokines are a family of small m.w. cytokines that induce chemotaxis and chemokinesis of leukocytes. These molecules are ligands for seven-transmembrane, Gi protein-linked receptors that induce a signaling cascade in human T cells and provide costimulation for T cell activation, in addition to participating in transendothelial migration of leukocytes. To address the role of chemokines in the regulation of Th cell cytokine production, we utilized an OVA-specific TCR transgenic (Tg+) model. Cells stimulated through the TCR and incubated in the presence of macrophage inflammatory protein-1alpha (MIP-1alpha) showed enhanced IFN-gamma production, whereas cells incubated in the presence of monocyte chemotactic protein-1 (MCP-1) showed enhanced IL-4 production. Similar results were obtained whether TCR Tg+ T cells were stimulated with anti-CD3 mAb or OVA peptide. Primary stimulation of T cells in the presence of chemokines, followed by secondary stimulation and tertiary stimulation with anti-TCR clonotype mAb alone (no exogenous chemokines), revealed an enhanced IFN-gamma production for MIP-1alpha stimulation and IL-4 production for MCP-1 stimulation. Naive Tg+ T cells, obtained from Tg+ mice crossed to RAG-1-deficient mice, showed enhanced IFN-gamma production when incubated with MIP-1alpha and enhanced IL-4 production when incubated with MCP-1. These results suggest CC chemokines play a role in regulating naive Th cell cytokine production, in addition to regulating leukocyte trafficking.
HIV-1 env DNA vaccine administered to rhesus monkeys elicits MHC class II-restricted CD4+ T helper cells that secrete IFN-gamma and TNF-alpha.
Authors: Lekutis C , Shiver J W , Liu M A , Letvin N L 
Published: December 2022

Abstract
The Th cell response elicited by an HIV-1 env plasmid DNA vaccine was assessed in rhesus monkeys by isolation of gp120-specific, MHC class II-restricted CD4+ T cell lines from PBL of vaccinated animals. The Env-specific CD4+ T cell lines recognized epitopes located in the second hypervariable region and in the carboxyl terminus of HIV-1 gp120. These cell lines proliferated in response to APC in the presence of recombinant gp120, as well as to APC expressing virally encoded Env. All of the CD4+ T cell lines responded to Env peptide by secreting IFN-gamma and TNF-alpha without appreciable IL-4 production. Recombinant gp120 stimulation of PBL from these vaccinated monkeys elicited the secretion of a similar profile of cytokines. Demonstration of a nucleotide vaccine eliciting a Th1-like immune response is consistent with the well documented ability of naked DNA vaccines to induce durable CD8+ CTL responses.
The dominant role of bone marrow-derived cells in CTL induction following plasmid DNA immunization at different sites.
Authors: Iwasaki A , Torres C A , Ohashi P S , Robinson H L , Barber B H 
Published: December 2022

Abstract
Although plasmid DNA immunization provides an effective means of inducing CTL responses to an expressed Ag, the mechanism by which CTL precursors are activated remains to be established. Insights could be gained by identifying the cells responsible for Ag presentation when DNA is introduced into different tissue sites. By immunizing parent into F1 bone marrow chimeric mice with an influenza nucleoprotein-expressing plasmid, we have demonstrated that the key cells in this presentation process for both gene gun-mediated epidermal injection and needle intramuscular injection of plasmid DNA are bone marrow derived. Furthermore, as assessed by intramuscular injection, coexpression of nucleoprotein with the costimulatory molecule B7-2, or the cytokines granulocyte-macrophage CSF and IL-12, did not convert nonhemopoietic cells into APCs. Thus, for two distinctly different modes of DNA immunization, in one case with or without coexpressed immunostimulatory factors, the APCs were consistently found to be of hemopoietic origin.
Refocusing neutralizing antibody response by targeted dampening of an immunodominant epitope.
Authors: Garrity R R , Rimmelzwaan G , Minassian A , Tsai W P , Lin G , de Jong J J , Goudsmit J , Nara P L 
Published: December 2022

Abstract
Immunodominant epitopes are known to suppress a primary immune response to other antigenic determinants by a number of mechanisms. Many pathogens have used this strategy to subvert the immune response and may be a mechanism responsible for limited vaccine efficacies. HIV-1 vaccine efficacy appears to be complicated similarly by a limited, immunodominant, isolate-restricted immune response generally directed toward determinants in the third variable domain (V3) of the major envelope glycoprotein, gp120. To overcome this problem, we have investigated an approach based on masking the V3 domain through addition of N-linked carbohydrate and reduction in net positive charge. N-linked modified gp120s were expressed by recombinant vaccinia virus and used to immunize guinea pigs by infection and protein boosting. This modification resulted in variable site-specific glycosylation and antigenic dampening, without loss of gp120/CD4 binding or virus neutralization. Most importantly, V3 epitope dampening shifted the dominant type-specific neutralizing Ab response away from V3 to an epitope in the first variable domain (V1) of gp120. Interestingly, in the presence of V3 dampening V1 changes from an immunodominant non-neutralizing epitope to a primary neutralizing epitope with broader neutralizing properties. In addition, Ab responses were also observed to conserved domains in C1 and C5. These results suggest that selective epitope dampening can lead to qualitative shifts in the immune response resulting in second order neutralizing responses that may prove useful in the fine manipulation of the immune response and in the development of more broadly protective vaccines and therapeutic strategies.
Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response.
Authors: Dalal M , Kim S , Voskuhl R R 
Published: December 2022

Abstract
Female SJL mice are more susceptible than male mice to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP)-specific T lymphocytes. In the present study, we examined mechanisms involved in this gender-related difference in disease susceptibility. MBP-specific T lymphocytes derived from spleens of males during the effector phase of adoptive EAE produced significantly higher levels of IL-10, an anti-inflammatory cytokine in EAE. A protective effect of testosterone was then shown. Females implanted with dihydrotestosterone pellets demonstrated a significantly less severe course of EAE as compared with females implanted with placebo pellets. Finally, MBP-specific T lymphocytes derived from dihydrotestosterone-implanted females produced significantly higher levels of IL-10 than those from placebo. Together these data indicate that testosterone exerts a protective effect in EAE that is mediated at least in part by enhanced production of IL-10 by autoantigen-specific T lymphocytes.
Macrophage inflammatory protein-1alpha (MIP-1alpha) is required for the efferent phase of pulmonary cell-mediated immunity to a Cryptococcus neoformans infection.
Authors: Huffnagle G B , Strieter R M , McNeil L K , McDonald R A , Burdick M D , Kunkel S L , Toews G B 
Published: December 2022

Abstract
Our objective was to define the role of the chemokine macrophage-inflammatory protein-1alpha (MIP-1alpha) in the efferent phase of pulmonary cell-mediated immunity (CMI) against Cryptococcus neoformans. Following intratracheal inoculation of C. neoformans (24067) into CBA/J mice, the development of CMI was required for leukocyte recruitment into the lungs at 2 wk postinfection. MIP-1alpha mRNA was expressed by day 6 postinfection, and MIP-1alpha protein in bronchoalveolar lavage fluid was detectable at day 6, but significantly elevated at days 19 and 33. Administration of neutralizing anti-MIP-1alpha Abs from days 7 to 13 blocked the increase in bronchoalveolar lavage fluid MIP-1alpha and resulted in a 37% decrease in total leukocytes in the lungs at day 16. There were 66% fewer macrophages/monocytes and 42% fewer neutrophils in the lungs of anti-MIP-1alpha-treated mice, and the pulmonary burden of C. neoformans was threefold higher. There was no significant difference in the number of eosinophils, CD4+, CD8+, or B220+ lymphocytes between the two groups of mice. Neutralization of MIP-1alpha did not significantly decrease the levels of monocyte chemotactic protein-1 (MCP-1); however, neutralization of MCP-1 significantly decreased MIP-1alpha levels, demonstrating that induction of MIP-1alpha was largely dependent on MCP-1 production. Neutralization of MIP-1alpha also blocked the cellular recruitment phase of a recall response to cryptococcal Ag in the lungs of immunized mice. Thus, in both the contexts of active cryptococcal infection or rechallenge with cryptococcal Ag, MIP-1alpha was required during the efferent phase of CMI for maximal leukocyte recruitment into the lungs, most notably the recruitment of phagocytic effector cells (neutrophils and macrophages).
Differential CD45 isoform expression accompanies reduced natural antibody binding in L5178Y-F9 tumor progression.
Authors: Zhang Z Y , Chow D A 
Published: December 2022

Abstract
Considerable evidence supports a role for polyclonal serum natural Ab (NAb) as a mediator of natural resistance against tumors. However, the molecular mechanisms of this NAb activity are not known. Flow cytometry selection of L5178Y-F9 murine T lymphoma cells for high NAb binding provided the variant LYNAb+, which exhibited an inversely corresponding reduction in tumorigenicity. Accompanying the increased NAb binding, LYNAb+ bound more monoclonal 14.8 anti-CD45RA and DNL-1.9 anti-CD45RC and less 13/2 anti-pan CD45, and the binding of MB23G2 anti-CD45RB was eliminated. However, neuraminidase treatment increased NAb binding and detection of pan CD45, CD45RA, and CD45RC but reduced CD45RB expression, suggesting that the epitopes recognized by the former Abs are masked by sialic acid, while the latter includes sialic acid. Growth of the LYNAb+ from a threshold s.c. inoculum in syngeneic DBA/2 mice yielded more tumorigenic cells which bound less NAb, anti-CD45RA, and anti-CD45RC; the same very low anti-CD45RB; and more anti-pan CD45. In accord with the mAb binding, the L5178Y-F9 and an in vivo passaged LYNAb+ variant expressed predominantly lower m.w. CD45 isoforms while the LYNAb+ expressed predominantly higher 200-kDa isoforms. The consistent correspondence between CD45RA and CD45RC determinant expression, CD45 isoform expression, tumorigenicity, and NAb binding exhibited by T lymphoma cells selected for high NAb binding in vitro or through tumor progression in vivo suggests that asialo high m.w. isoforms of the cell surface-signaling molecule CD45 are differentially expressed during tumor development and furthermore that they participate in NAb-mediated antitumor mechanisms.
A mechanism for selective recruitment of CD8 T cells into B7-1-transfected plasmacytoma: role of macrophage-inflammatory protein 1alpha.
Authors: Maric M , Chen L , Sherry B , Liu Y 
Published: December 2022

Abstract
An important aspect of immunity is the recruitment and accumulation of lymphocytes into target tissues where Ags are localized. Because the TCR recognizes antigenic peptides presented by MHC molecules, the subset of T cells that exert effector function is determined by the class of MHC molecules expressed on a given tissue. We and others have demonstrated that CD8 T cells are preferentially recruited into B7-1-transfected class II-negative plasmacytoma J558, and the virus-infected central nervous system. However, the mechanism for such specificity has not been addressed. Here we analyzed the mechanism for selective recruitment of CD8 T cells into B7-1-transfected plasmacytoma J558. We show that sustained accumulation of CD8 T cells in vivo requires local expression of B7-1. In addition, we have observed a striking correlation between expression of macrophage-inflammatory protein 1alpha (MIP1alpha) and selective accumulation of CD8 T cells in the tumors. The selective recruitment of CD8 T cells is blocked by in vivo administration of neutralizing anti-MIP1alpha antisera. Moreover, gene-transfer studies reveal that locally produced MIP1alpha is sufficient to induce selective recruitment of CD8 T cells. Taken together, our study reveals that costimulation by B7 leads to sustained local production of MIP1alpha, which selectively recruits CD8 T cells into tumors. These results have important implications for T cell recruitment in vivo and for tumor immunotherapy.