Peripheral tolerance in T cell receptor‐transgenic mice: Evidence for T cell anergy

Falb, Dean; Briner, Thomas J.; Sunshine, Geoffrey H.; Bourque, Cheryl R.; Luqman, Mohammad; Gefter, Malcolm L.; Kamradt, Thomas

doi:10.1002/eji.1830260120

Cited by 49 publications

(43 citation statements)

References 46 publications

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“…However, if that elimination were to be attempted, it would have to be done under cover of agents, such as anti-cytokine antibodies, that could block the potentially dangerous effects of the transient burst of cytokine production that occurs. Indeed, Gefter and his colleagues had attempted to deplete cells mediating atopic responses by treating animals and humans with peptides containing epitopes of key allergens (14,15). Although they concluded that the mechanism responsible for diminution of responses by challenge with specific peptides was anergy rather than elimination, they actually performed their key experiments with naive rather than memory T cells.…”

Section: Discussionmentioning

confidence: 99%

Antigen challenge leads toin vivoactivation and elimination of highly polarized TH1 memory T cells

Hayashi

Liu

Min

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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TH1 memory T cells derived from T cell receptor transgenic mice, in which the T cell antigen receptor is specific for a cytochrome C peptide in association with I-E k , were transferred into normal B10.A mice and allowed to adopt a resting phenotype. When challenged, 30 -60 days after transfer, with i.v. cytochrome C, the transgenic cells rapidly became activated, expressed mRNA for IFN␥, and began to divide. However, after 48 h, the frequency of the cells fell progressively, reaching levels only slightly above the limit of detection by day 8 and thereafter remain depressed for up to 90 days. The remaining cells were anergic as shown by limitation in proliferation and IFN␥ production in response to in vitro antigen stimulation. Even if challenged with antigen emulsified in complete Freund's adjuvant, the overall pattern was similar, except that in the draining lymph nodes, the surviving antigen-specific cells were not anergic, although spleen cells were still strikingly anergic. Thus, antigenic challenge of mice possessing resting memory TH1 CD4 T cells leads to the unanticipated loss of most of the specific cells and an apparent depletion rather than enhancement of immunologic memory.tolerance ͉ TH1 cells ͉ anergy ͉ immunologic memory ͉ apoptosis

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Section: Discussionmentioning

confidence: 99%

Antigen challenge leads toin vivoactivation and elimination of highly polarized TH1 memory T cells

Hayashi

Liu

Min

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…AICD triggered in transformed T cells and T cell hybridomas by stimulation of the CD3/TCR complex is mediated via the induction of FasL expression and subsequent interaction of FasL with the Fas Ag (3)(4)(5). The maintenance of peripheral tolerance is a multistep process that may involve functional "anergy" down-modulation of cell surface TCR expression (47,48). Stimulation of activated T cells up-regulates the expression of the FasL, and the interaction of FasL with the corresponding Fas receptor triggers an apoptosis program that culminates in cellular suicide usually associated with the fragmentation of DNA into oligonucleosomal bands (Fig.…”

Section: Discussionmentioning

confidence: 99%

Possible Role of Organ-Specific Autoantigen for Fas Ligand-Mediated Activation-Induced Cell Death in Murine Sjögren’s Syndrome

Ishimaru

Yanagi

Ogawa

et al. 2001

The Journal of Immunology

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Activation-induced cell death (AICD) is a well-known mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). In this study, we demonstrate that the administration of a soluble form of anti-FasL Ab, FLIM58, results in severe destructive autoimmune exocrinopathy in the murine model of human Sjögren’s syndrome (SS), and we found that an organ-specific autoantigen may play an important role on down-modulation of AICD. A high titer of serum autoantibodies against 120-kDa α-fodrin autoantigen was detected in the FLIM58-treated mice, and splenic T cell culture supernatants contained high levels of IFN-γ. In vitro T cell apoptosis assay indicated that FasL-mediated AICD is down-regulated by autoantigen stimulation in spleen cells from the murine SS model, but not from Fas-deficient MRL/lpr mice and FasL-deficient MRL/gld mice. FasL undergo metalloproteinase-mediated proteolytic processing in their extracellular domains, resulting in the release of soluble trimeric ligands (soluble FasL). We showed that the processing of soluble FasL occurs in autoantigen-specific CD4+ T cells, and that a significant increase in expressions of metalloproteinase-9 mRNA was observed in spleen cells from SS model mice. These findings indicate that the increased generation of soluble FasL inhibits the normal AICD process, leading to the proliferation of effector CD4+ T cells in the murine SS model.

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“…These include deletion or inactivation of mature peripheral T-and B-cells (anergy) due to not receiving costimulatory signals, ignorance of autoantigens, activation-induced cell death of autoreactive T-cells (AICD), as well as the toleranceinducing effect of regulatory T-lymphocytes (T regs ) and dendritic cells (DCs) [15]. T-cells that are unable to produce IL-2 upon en-countering the antigen cannot be completely activated and are called anergic [17,18]. Some of these anergic T-cells produce IL-10, which suppresses the activation of T-cells [19].…”

Section: Immune System Physiology and Autoimmune Responsesmentioning

confidence: 99%

Autoimmunity and Apoptosis - Therapeutic Implications

Rashedi

Panigrahi²,

Ezzati³

et al. 2007

CMC

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Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against pathogens, however, has been achieved at the expense of a higher risk for "self"-directed reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self" causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T-and B-lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions.

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Peripheral tolerance in T cell receptor‐transgenic mice: Evidence for T cell anergy

Cited by 49 publications

References 46 publications

Antigen challenge leads toin vivoactivation and elimination of highly polarized TH1 memory T cells

Antigen challenge leads toin vivoactivation and elimination of highly polarized TH1 memory T cells

Possible Role of Organ-Specific Autoantigen for Fas Ligand-Mediated Activation-Induced Cell Death in Murine Sjögren’s Syndrome

Autoimmunity and Apoptosis - Therapeutic Implications

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