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A K Abbas

Publications and source records attributed to A K Abbas.

At least 37 records · Page 2Linked to original sources
PubMed1998

The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens.

We have examined the role of Fas and Bcl-2 in T cell survival and responses to antigen in vivo using T cells that express a transgenic antigen receptor specific for hen egg lysozyme (HEL) and that either lack functional Fas or Fas ligand (FasL) or overexpress Bcl-2 as a transgene. HEL-specific, Bcl-2-transgenic T cells showed prolonged responses to immunization with cognate peptide but were eliminated rapidly when exposed to HEL expressed systemically as a self antigen. In contrast, Fas- and FasL-defective T cells did not display exaggerated responses to immunization with HEL peptide, but did show increased expansion and survival in response to systemic self antigen and were able to activate anti-HEL (self) antibody-forming cells. Thus, Bcl-2 and Fas play different roles in the regulation of T cell responses to antigen in vivo and in self tolerance.

Adoptive Transfer↗
PubMed1998

Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis.

Activation-induced cell death (AICD) of lymphocytes is an important mechanism of self-tolerance. In CD4+ T cells, AICD is mediated by the Fas pathway and is enhanced by IL-2. To define the mechanisms of this pro-apoptotic action of IL-2, we analyzed CD4+ T cells from wild-type and IL-2-/- mice expressing a transgenic T cell receptor. T cells become sensitive to AICD after activation by antigen and IL-2. IL-2 increases transcription and surface expression of Fas ligand (FasL) and suppresses transcription and expression of FLIP, the inhibitor of apoptosis. The ability of IL-2 to enhance expression of a pro-apoptotic molecule, FasL, and to suppress an inhibitor of Fas signaling, FLIP, likely accounts for the role of this cytokine in potentiating T cell apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Role of cytokines in autoimmunity.

Activation-induced apoptosis of T lymphocytes is an important mechanism for maintaining self-tolerance. The sensitivity of T cells to apoptosis by the Fas pathway is regulated by the exposure of these cells to different cytokines. IL-2 is a survival and growth factor for T cells, as well as a necessary potentiator of Fas-mediated cell death. The role of this cytokine in triggering death pathways is the likely explanation for the autoimmune disease that develops as a result of targeted disruption of the IL-2 or IL-2 receptor alpha or beta chain gene.

Animals↗
PubMed1997

Functional consequences of dysregulated B7-1 (CD80) and B7-2 (CD86) expression in B or T lymphocytes of transgenic mice.

T cell activation and tolerance are regulated by interactions between CD28 or CTLA-4 on T cells and B7 costimulatory molecules on APCs. We have generated transgenic mouse strains that constitutively express B7-1 (CD80) at high levels on B cells or T cells or express B7-2 (CD86) on T lymphocytes to examine the consequences of dysregulated B7 expression on T cell responses. The transgene-derived B7 molecules are functional, because B7-1 transgenic B cells are more efficient APCs than are wild-type B cells, and the activation of B7 transgenic T cells is less dependent on exogenous costimulation than that of wild-type T cells. In vivo, constitutive expression of B7 molecules leads to the elimination of immature B cells. The expression of B7 molecules on thymocytes results in the down-regulation of CD28 expression. However, B7 transgenic mice have normal numbers of mature lymphocytes and mount normal T cell responses following immunization with protein Ag. Neither anergy induction nor superantigen-mediated deletion of T cells is altered by the dysregulated expression of B7-1 or B7-2 on B or T lymphocytes in these transgenic strains. Therefore, functionally significant levels of B7 expressed constitutively on mature lymphocytes are not, by themselves, sufficient to abrogate T cell tolerance or induce autoimmune disease.

Animals↗
PubMed1997

Role of interleukin 12 and costimulators in T cell anergy in vivo.

The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti-CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti-CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one.

Abatacept↗
PubMed1997

Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor.

IL-2 was initially defined as a T lymphocyte growth factor, but recent studies have provided evidence that it may also play a role in regulating T cell differentiation, apoptosis, and tolerance. To examine the contribution of IL-2 to these processes, we have bred a class II-restricted TCR transgene into mice deficient in the alpha-chain of the IL-2R, CD25. We show that in response to Ag, T cells from these mice are unable to use IL-2 and, as a result, are less efficient at traversing the cell cycle, and proliferate less than wild-type cells. Furthermore, CD25 -/- T cells exhibit reduced survival in vitro, even in the presence of costimulatory signals. IL-4 and IL-15, a cytokine related to IL-2, enhance the survival and Ag-induced proliferation of CD25 -/- T cells. Activated CD25 -/- T cells are resistant to Fas-mediated activation-induced cell death (AICD), and this defect cannot be corrected by other cytokines. Therefore, IL-2 plays a unique role in regulating AICD, but has redundant roles in T cell survival and proliferation in vitro. The failure of AICD observed with CD25 -/- T cells may explain the unexpected observation that deficiency of IL-2 or of the alpha- or beta-chain of the IL-2R results not in immunodeficiency, but in autoimmune disease.

Animals↗
PubMed1997

T-cell subsets: recruiting the right kind of help.

The qualitative features of immune responses are influenced by the polarization of helper T cells towards two distinct phenotypes, Th1 and Th2. Recent evidence suggests that these helper cell subsets may be differentially recruited to the sites of different types of inflammatory reaction.

Animals↗
PubMed1997

Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86.

For T cells to be optimally activated, recognition of Ag/MHC complexes by the TCR must be accompanied by a second, costimulatory signal that can be provided efficiently by the related costimulatory molecules CD80 (B7-1) and CD86 (B7-2). Recently, CD80 and CD86 have been implicated as differential determinants of Th1- vs Th2-type cytokine profiles. However, this remains a controversial issue since conflicting results have been obtained in different experimental models both in vivo and in vitro. To investigate the role of CD80 and CD86 in Th subset differentiation, we have examined the cytokine profiles induced in TCR transgenic T cells stimulated by peptide in association with splenic APCs obtained from knockout mice that selectively lack expression of either the CD80 or the CD86 molecule. Our data suggest that CD86, and to a lesser extent CD80, can make significant contributions to the production of both IL-4 and IFN-gamma. However, neither molecule plays an obligatory role in priming for the production of either effector cytokine. Furthermore, CD80 and CD86 contribute to the magnitude of T cell activation, but do not appear to selectively regulate Th1 vs Th2 differentiation.

Amino Acid Sequence↗
PubMed1997

Bicarbonate-sensitive cysteine induced elevation of extracellular aspartate and glutamate in rat hippocampus in vitro.

The effect of different concentrations of cysteine (0.125, 0.25, 0.5 and 1 mM) on the net efflux of endogenous amino acids was studied by the incubation of rat hippocampal slices. Addition of cysteine (1 mM) in bicarbonate containing low K+ medium (5 min) selectively increased the basal net efflux of glutamate and aspartate by 370% and 396%, respectively. High K+ media (50 mM) containing cysteine (1 mM) evoked the net efflux of glutamate and aspartate by 1454% and 1019%, respectively. The corresponding effects in control slices without cysteine were 669% and 404%, respectively. No changes were observed on the concentrations of GABA, glutamine and taurine. The cysteine oxidation products, cysteine sulfinate (0.5 microM) and cystine (0.25 mM) were without effects. The effect of cysteine (0.5 mM) was dramatically reduced in media with no added bicarbonate/CO2. Thus, cysteine in a bicarbonate-sensitive manner selectively increases the extracellular concentration of excitotoxic amino acids in adult rat brain in vitro, possibly by interfering with the carrier-mediated glutamate uptake/release.

Animals↗
PubMed1997

Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement.

Studies of T cell anergy in vitro have led to the widely accepted view that anergy is induced by T cell antigen recognition without costimulation. We show that the induction of T cell anergy in vivo is due to an abortive T cell response that requires recognition of B7 molecules, since blocking B7 maintains T cells in an unactivated but functionally competent state. Furthermore, the induction of anergy is prevented by blocking CTLA-4, the inhibitory T cell receptor for B7 molecules. Thus, in vivo T cell anergy may be induced not because of a lack of costimulation, but as a result of specific recognition of B7 molecules by CTLA-4. In contrast, blocking CD28 on T cells prevents priming but not the induction of tolerance. Therefore, the outcome of antigen recognition by T cells is determined by the interaction of CD28 or CTLA-4 on the T cells with B7 molecules.

Abatacept↗
PubMed1996

Functional diversity of helper T lymphocytes.

The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses. Defining the cellular and molecular mechanisms of helper-T-cell differentiation should lead to rational strategies for manipulating immune responses for prophylaxis and therapy.

Animals↗
PubMed1996

Cytokine transcriptional events during helper T cell subset differentiation.

The molecular basis for changes in cytokine expression during T helper (Th) cell subset differentiation is not well understood. We have characterized transcriptional events related to cytokine gene expression in populations of naive T cell receptor-transgenic T cells as they are driven in vitro toward Th1 or Th2 phenotypes by interleukin (IL)-12 or IL-4 treatment, respectively. Quantitative reverse transcriptase-polymerase chain reaction analysis of cytokine transcripts indicates that interferon (IFN) gamma, IL-4, and IL-2 mRNA are expressed with distinct kinetics after naive T cells are stimulated with antigen and either IL-4 or IL-12. IFN-gamma mRNA appears as early as 6 h in IL-12-treated cultures, IL-4 appears only after 48 h in IL-4-treated cultures, and IL-2 is equivalently expressed in both types of cultures. Analyses were performed to determine if there were any differences in activation of IL-2 or IL-4 transcription factors that accompanied Th1 versus Th2 differentiation. These studies demonstrated that signal transducer and activator of transcription 6 (STAT6) binds to a sequence in the IL-4 promoter and that this STAT6-binding site can support IL-4-dependent transcription of a linked heterologous promoter. Prolonged activation of STAT6 is characteristic of populations undergoing Th2 differentiation. Furthermore, STAT6 is activated in an autocrine manner when differentiated Th2 populations are stimulated by antigen receptor ligation. Th1 populations derived from IL-12 plus antigen treatment of naive T cells remain responsive to IL-4 as indicated by induction of STAT6 and IL-4 mRNA. These data indicate that Th1 and Th2 differentiation represents the combination of different, apparently independently regulated transcriptional events. Furthermore, among transcription factors that bind to the IL-4 or IL-2 promoters, STAT6 is the one whose activation distinguishes Th2 versus Th1 development.

Animals↗
PubMed1996

T cell responses in calcineurin A alpha-deficient mice.

We have created embryonic stem (ES) cells and mice lacking the predominant isoform (alpha) of the calcineurin A subunit (CNA alpha) to study the role of this serine/threonine phosphatase in the immune system. T and B cell maturation appeared to be normal in CNA alpha -/- mice. CNA alpha -/- T cells responded normally to mitogenic stimulation (i.e., PMA plus ionomycin, concanavalin A, and anti-CD3 epsilon antibody). However, CNA alpha -/- mice generated defective antigen-specific T cell responses in vivo. Mice produced from CNA alpha -/- ES cells injected into RAG-2-deficient blastocysts had a similar defective T cell response, indicating that CNA alpha is required for T cell function per se, rather than for an activity of other cell types involved in the immune response. CNA alpha -/- T cells remained sensitive to both cyclosporin A and FK506, suggesting that CNA beta or another CNA-like molecule can mediate the action of these immunosuppressive drugs. CNA alpha -/- mice provide an animal model for dissecting the physiologic functions of calcineurin as well as the effects of FK506 and CsA.

Animals↗
PubMed1996

IL-12, as an adjuvant, promotes a T helper 1 cell, but does not suppress a T helper 2 cell recall response.

IL-12 is a potent inducer of NK and cytolytic T cell activity, IFN-gamma production, and T cell proliferation, and is necessary for differentiation of naive T cells to the Th1 subset. We have previously shown that IL-12 promotes a primary Th1 response and suppresses a primary Th2 response in lymph nodes of mice primed with a model hapten-protein conjugate, 2,4,6-trinitrophenyl (TNP)-keyhole limpet hemocyanin (KLH). We have now extended these studies to determine the Th phenotype of the recall response following immunization with soluble Ag and IL-12. For these experiments, mice were primed with TNP-KLH with or without treatment with IL-12, allowed to progress beyond the primary immune response, and challenged by i.p. injection of TNP-KLH. The phenotype of the recall response was monitored by measuring ex vivo production of IFN-gamma and IL-4 in Ag-stimulated lymph node and spleen cell cultures. Titer and isotype of TNP-specific serum Abs were also evaluated. Mice primed with Ag+IL-12 developed a Th1 recall response, as detected by KLH-specific IFN-gamma production from cultured spleen cells and the presence of TNP-specific IgG2a Ab in serum. However, they also developed an Ag-specific Th2 recall response, as characterized by Ag-induced IL-4 production from spleen cells and the presence of high titers of anti-TNP IgG1 in the serum. Studies of the cytokine profile during the primary response revealed that IL-12 induced in spleen cells the capacity to express both IL-4 and IFN-gamma. CD4+ T cells are necessary for production of IL-4 in the spleens of IL-12-treated mice, and most likely account for the Th2 recall response detected in mice primed with Ag+IL-12. These results indicate that the Th1 phenotype induced by immunization with IL-12 and Ag is maintained so that a Th1 recall response is expressed upon subsequent challenge with Ag. However, immunization with IL-12 also supports the development of a Th2 recall response, indicating that the Th1-inducing effect of IL-12 in vivo is not accompanied by a long lasting suppression of Th2 development.

Adjuvants, Immunologic↗
PubMed1996

Role of Fas-mediated cell death in the regulation of immune responses.

Interaction of the cell-surface molecule Fas (CD95 APO-1) with its specific ligand triggers apoptotic death of T and B lymphocytes. This pathway is important for eliminating self-reactive lymphocytes and thus preventing autoimmunity. Fas is also involved in controlling injurious lymphocyte reactions in immunologically 'privileged' tissues, and may provide a strategy for reducing graft rejection.

Animals↗
PubMed1996

The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance.

Using cells from TCR transgenic mice that do or do not express Fas, we show that there are two mechanistically distinct forms of apoptosis in CD4+ T cells. Naive T cells undergo apoptosis if cultured in the absence of antigen or costimulation. This form of programmed cell death (PCD) is not dependent on Fas, and is prevented by CD28-mediated signals, which lead to the secretion of growth factors and the expression of survival genes, such as bcl-xL. Recently activated T cells undergo apoptotic death upon repeated stimulation. This activation-induced cell death (AICD) is mediated by Fas, but is independent of costimulation and is not prevented by IL-2 or bcl-xL. Finally, we show that peripheral tolerance may be induced in vivo independent of Fas-mediated cell death.

Animals↗