PubMed Health⌕ Search

Biomedical subjects

Abul K Abbas

Publications and source records attributed to Abul K Abbas.

29 records · Page 2Linked to original sources
PubMed2004

T cell tolerance and autoimmunity.

CD4 T cells are the master controllers of immune responses to protein antigens, and many autoimmune diseases are thought to arise from a breakdown of immunological tolerance in CD4 cells. Peripheral tolerance in CD4 T cells is maintained by several mechanisms, including functional anergy, deletion (death) by apoptosis and suppression by regulatory T lymphocytes (Treg). Using transgenic mouse models, we have explored the roles of these mechanisms in tolerance to cell-associated tissue-restricted self-antigens and secreted systemic self-antigens. Tolerance to a membrane form of the antigen expressed in islet beta cells is maintained by Treg, which block T cell differentiation into pathogenic effectors, and by CTLA-4, which increases the activation threshold of T cells and prevents responses to the self-antigen. A systemically produced soluble form of the antigen induces rapid T cell anergy followed by deletion. The induction of anergy does not require either CTLA-4 or Treg, although in the absence of Treg tolerance can be broken more readily by potent immunogenic signals. Encounter with circulating antigen in T cells induces a state of antigen receptor "desensitization" that is associated with a block in proximal receptor-triggered signals. Thus, different mechanisms play dominant roles in T cell tolerance to different types of self-antigens.

Animals↗
PubMed2003

Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo.

The failure of CD25+ regulatory T cells (Tregs) to proliferate after T cell receptor (TCR) stimulation in vitro has lead to their classification as naturally anergic. Here we use Tregs expressing a transgenic TCR to show that despite anergy in vitro, Tregs proliferate in response to immunization in vivo. Tregs also proliferate and accumulate locally in response to transgenically expressed tissue antigen whereas their CD25- counterparts are depleted at such sites. Collectively, these data suggest that the anergic state that characterizes CD25+ Tregs in vitro may not accurately reflect their responsiveness in vivo. These observations support a model in which Treg population dynamics are shaped by the local antigenic environment.

Animals↗
PubMed2003

The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens.

When antigen-presenting cells (APCs) encounter inflammatory stimuli, they up-regulate their expression of B7. A small amount of B7 is also constitutively expressed on resting APCs, but its function is unclear. Here we show that initiation of T cell responses requires the expression of B7 on immunizing APCs, but the responses are much greater in the absence of basal B7 expression. Transfer of antigen-specific CD4+CD25+ cells reverses the increased responsiveness, and tolerance to a self-protein is broken by immunization in the absence of basal B7, thereby inducing autoimmunity. Similar loss of self-tolerance is seen on depletion of CD25+ cells. Thus, constitutively expressed B7 costimulators function to suppress T cell activation and maintain self-tolerance, principally by sustaining a population of regulatory T cells.

Abatacept↗
PubMed2003

The activation of lymphocytes is in their CARMA.

Lymphocyte activation via antigen receptors initiates adaptive immune responses. Two papers in this issue of Immunity demonstrate that CARMA-1, a CARD carrying member of the MAGUK family proteins, is essential for lymphocyte activation. CARMA-1 functions by coupling antigen receptor signals to NF-kappaB induction and JNK activation.

Animals↗
PubMed2003

The control of T cell activation vs. tolerance.

B7 costimulators and the T cell growth factor IL-2 are important stimuli for the activation of T lymphocytes and the development of effective immune responses. Recent studies show that the same signals promote the development of regulatory T cells or the apoptotic death of activated T cells, and thus, function to terminate immune responses and maintain self-tolerance. The balance between the different outcomes of the same signals may be determined by the magnitude of these signals and the presence or absence of concomitant stimuli, such as those generated during innate immune responses to microbes.

Animals↗
PubMed2003

Natural versus adaptive regulatory T cells.

The regulation of immune responses to self-antigens is a complex process that involves maintaining self-tolerance while retaining the capacity to mount robust immune responses against invading microorganisms. Over the past few years, many new insights into this process have been gained, leading to the re-emergence of the idea that regulatory T (T(Reg)) cells are a central mechanism of immune regulation. These insights have raised fundamental questions concerning what constitutes a T(Reg) cell, where they develop and what signals maintain T(Reg)-cell populations in a functional state. Here, we propose the existence of two subsets of CD4+ T(Reg) cells--natural and adaptive--that differ in terms of their development, specificity, mechanism of action and dependence on T-cell receptor and co-stimulatory signalling.

Animals↗
PubMed2002

CTLA-4 differentially regulates T cell responses to endogenous tissue protein versus exogenous immunogen.

CTLA-4 is critical to the regulation of CD4 T cell homeostasis in vivo. However, whether CTLA-4 regulates responses to both self and foreign proteins is not clear. We have directly compared the role of CTLA-4 in controlling T cell responses to the same protein presented as an endogenous tissue Ag vs a foreign immunizing Ag. We show that CTLA-4 only modestly reduces responses to Ag administered with adjuvant, but dramatically inhibits responses to the same Ag expressed transgenically as a tissue self protein. The critical consequence of CTLA-4 engagement is to inhibit T cell accumulation in the local lymph node draining the Ag-bearing tissue, and failure of this control leads to the onset of autoimmune tissue destruction. Thus, CTLA-4 may preferentially dampen pathologic immune responses to self proteins while permitting protective immunity to foreign agents.

Abatacept↗
PubMed2002

Interferon gamma is required for activation-induced death of T lymphocytes.

The effector cytokine interferon gamma (IFN-gamma) may play a role in T cell homeostasis. We have examined the requirement for IFN-gamma in one mechanism that regulates T cell expansion and survival, activation-induced cell death (AICD). CD4(+) T cells lacking IFN-gamma or the Stat1 transcription factor are resistant to AICD. IFN-gamma is required for the production of caspases, and retrovirus-mediated expression of caspase-8 restores the sensitivity of Stat1-deficient T cells to AICD. In vitro, IFN-gamma limits the expansion of T cells that are stimulated through their antigen receptors. Thus, IFN-gamma may function to control the expansion and persistence of T cells by promoting caspase-8-dependent apoptosis.

Animals↗
PubMed2002

The enemy within: keeping self-reactive T cells at bay in the periphery.

The remarkable capacity of the mammalian immune system to coordinate deadly attacks against numerous invading pathogens, yet turn a blind eye to self-tissues continues to fascinate immunologists. It has been clear for some time that immune cells capable of recognizing self-proteins exist in normal individuals without seemingly causing harm. The 'peripheral tolerance' mechanisms that keep these cells in check are the focus of intense research, not least because defects in these pathways might cause autoimmune diseases. In this review, new developments in our understanding of peripheral tolerance are discussed.

Animals↗
PubMed2002

Functional tolerance is maintained despite proliferation of CD4 T cells after encounter with tissue-derived antigen.

Since negative selection in the thymus is incomplete, some self-reactive T cells are able to mature and seed the periphery. To study how these T cells interact following encounter with the self-protein they recognize in the periphery, we have developed an adoptive transfer system in which HEL-specific TCR transgenic CD4 T cells are transferred to mice expressing HEL protein in the pancreas under the control of the rat insulin promoter. Here we show that after adoptive transfer of HEL-specific T cells functional tolerance is maintained despite evidence that the T cells encounter and respond to pancreas-expressed antigen. Even the provision of an additional activation stimulus by peripheral immunization with HEL protein is insufficient to induce the T cells to cause autoimmune tissue injury. However, in the presence of blocking anti-CTLA-4-mAb, immunized adoptive transfer recipients rapidly developed diabetes. These data suggest that the CTLA-4 pathway regulates the pathogenicity of antigen-specific T cells following a peripheral activation stimulus.

Adoptive Transfer↗