T Cell-Mediated Maintenance of Natural Self-Tolerance: its Breakdown as a Possible Cause of Various Autoimmune Diseases

Sakaguchi, Shimon; Toda, Masaaki; Asano, Masanao; Itoh, Masae; Morse, Stephen S.; Sakaguchi, Noriko

doi:10.1006/jaut.1996.0026

Cited by 235 publications

(215 citation statements)

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“…Similar phenomena have been described using rat T cells in vitro; a requirement for the presence of APC for this inhibition to be observed was also noted in this study (23). The third set of related findings have emerged from the study of day three thymectomized mice that develop a variety of autoimmune pathologies spontaneously (12), and lack a small population of CD4 ϩ , CD25 ϩ peripheral T cells. The significance of these cells became apparent when they were adoptively transferred from a normal, into a day three thymectomized mouse, in that they protected the recipients from the onset of autoimmune disease.…”

Section: Discussionsupporting

confidence: 84%

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Anergic T Cells Inhibit the Antigen-Presenting Function of Dendritic Cells

Vendetti

Chai

Dyson

et al. 2000

The Journal of Immunology

147

103

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The phenomena of infectious tolerance and linked-suppression are well established, but the mechanisms involved are incompletely defined. Anergic T cells can inhibit responsive T cells in vitro and prolong skin allograft survival in vivo. In this study the mechanisms underlying these events were explored. Allospecific mouse T cell clones rendered unresponsive in vitro inhibited proliferation by responsive T cells specific for the same alloantigens. The inhibition required the presence of APC, in that the response to coimmobilized anti-CD3 and anti-CD28 Abs was not inhibited. Coculture of anergic T cells with bone marrow-derived dendritic cells (DC) led to profound inhibition of the ability of the DC to stimulate T cells with the same or a different specificity. After coculture with anergic T cells expression of MHC class II, CD80 and CD86 by DC were down-regulated. These effects did not appear to be due to a soluble factor in that inhibition was not seen in Transwell experiments, and was not reversed by addition of neutralizing anti-IL-4, anti-IL-10, and anti-TGF-β Abs. Taken together, these data suggest that anergic T cells function as suppressor cells by inhibiting Ag presentation by DC via a cell contact-dependent mechanism.

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Section: Discussionsupporting

confidence: 84%

“…In addition, we have reported that anergic donor-specific T cells can prolong the survival of skin allografts in vivo (10). Related phenomena have been reported by other groups in human (11) and murine systems (12,13).…”

Section: Anergic T Cells Inhibit the Antigen-presenting Function Ofsupporting

confidence: 81%

Anergic T Cells Inhibit the Antigen-Presenting Function of Dendritic Cells

Vendetti

Chai

Dyson

et al. 2000

The Journal of Immunology

147

103

View full text Add to dashboard Cite

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“…The suppression activity of the dual APL could be adoptively transferred by splenocytes of dual-APL-treated mice (7). Furthermore, the CD4 ϩ CD25 ϩ regulatory T cells that are known to play a critical role in the maintenance of peripheral tolerance (8) were found to be functionally involved in the suppressive action of the dual APL (9,10).…”

mentioning

confidence: 99%

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Ben-David¹,

Aruna²,

Seger

et al. 2006

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

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Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are T cell-dependent antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259 -271, down-regulated in vitro and in vivo MG-associated autoreactive responses. The dual APL was shown to exert its beneficial effects by up-regulating ERK1,2 in CD4 ؉ CD25 ؉ regulatory cells. In this study, we investigated a novel 50-kDa ERK-like protein (ERK-50) that is up-regulated significantly in addition to ERK1,2 after treatment with the dual APL. We report here that ERK-50 was upregulated in LN cells and in LN-derived T cells of mice that were immunized with the myasthenogenic peptides and treated with the dual APL. Moreover, ERK-50 was up-regulated in dual-APLtreated mice that were immunized with the Torpedo acetylcholine receptor. ERK-50 was demonstrated to be recognized by antibodies directed against the C and N termini of ERK1, against the C terminus of ERK2, and against general ERK. The 50-kDa ERK was shown to be stimulated by Con A, and inhibition of MEK1 down-regulated the 50-kDa ERK as was shown for ERK1,2. However, 4␤-phorbol 12-myristate 13-acetate (TPA) did not stimulate ERK-50. Finally, the activated ERK-50 was up-regulated in the dual-APL-induced CD4 ؉ CD25 ؉ regulatory cells. Thus, ERK-50 is suggested to be a novel ERK isoform, being up-regulated in response to treatment with the dual APL.autoimmunity ͉ immunomodulation ͉ kinase

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“…Foxp3 + regulatory T cells (Tregs) produce immunosuppressive cytokines, such as TGF-β, IL-10, and IL-35 and maintain peripheral auto-tolerance (23,24). Decreased TGF-β production may be, at least in part, due to decreased number of Tregs.…”

Section: Discussionmentioning

confidence: 99%