CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Verhagen, Johan; Genolet, RaphaÃ«l; Britton, Graham J.; Stevenson, Brian J.; Sabatos-Peyton, Catherine; Dyson, Julian; Luescher, Immanuel F.; Wraith, David C.

doi:10.1073/pnas.1208573110

Cited by 46 publications

(33 citation statements)

References 60 publications

(82 reference statements)

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“…On the other hand, Treg-specific CTLA-4 deficiency cancelled physiological selfskewing of their TCR repertoire. In addition, CTLA-4-deficient TCR transgenic mice bore an altered TCR repertoire in both Treg and Tconv cells (54). These findings when taken together indicate that a common CTLA-4-dependent mechanism of TCR self-skewing operates in developing Foxp3…”

Section: Discussionmentioning

confidence: 62%

Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression

Yamaguchi¹,

Kishi

Osaki

et al. 2013

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

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Thymus-produced CD4+ regulatory T (Treg) cells, which specifically express the transcription factor forkhead box p3, are potently immunosuppressive and characteristically possess a self-reactive T-cell receptor (TCR) repertoire. To determine the molecular basis of Treg suppressive activity and their self-skewed TCR repertoire formation, we attempted to reconstruct these Treg-specific properties in conventional T (Tconv) cells by genetic manipulation. We show that Tconv cells rendered IL-2 deficient and constitutively expressing transgenic cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) were potently suppressive in vitro when they were preactivated by antigenic stimulation. They also suppressed in vivo inflammatory bowel disease and systemic autoimmunity/ inflammation produced by Treg deficiency. In addition, in the thymus, transgenic CTLA-4 expression in developing Tconv cells skewed their TCR repertoire toward higher self-reactivity, whereas CTLA-4 deficiency specifically in developing thymic Treg cells cancelled their physiological TCR self-skewing. The extracellular portion of CTLA-4 was sufficient for the suppression and repertoire shifting. It interfered with CD28 signaling to responder Tconv cells via outcompeting CD28 for binding to CD80 and CD86, or modulating CD80/CD86 expression on antigen-presenting cells. Thus, a triad of IL-2 repression, CTLA-4 expression, and antigenic stimulation is a minimalistic requirement for conferring Treg-like suppressive activity on Tconv cells, in accordance with the function of forkhead box p3 to strongly repress IL-2 and maintain CTLA-4 expression in natural Treg cells. Moreover, CTLA-4 expression is a key element for the formation of a self-reactive TCR repertoire in natural Treg cells. These findings can be exploited to control immune responses by targeting IL-2 and CTLA-4 in Treg and Tconv cells.immune tolerance | CD25 | thymic selection

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Section: Discussionmentioning

confidence: 62%

Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression

Yamaguchi¹,

Kishi

Osaki

et al. 2013

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

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“…However, it has been shown that CTLA-4 deficiency affects both conventional T cells and Treg cells by altering TCR Vα and Jα segments and the CDR3α composition in TCR transgenic mice (36). In support, overexpression of CTLA-4 was shown to favor self-skewing of the Treg cell TCR repertoire as clonal deletion in response to endogenous superantigens was reduced (48).…”

Section: Ctla-4-deficient Thymocytes and Peripheral T Cells Cause Difmentioning

confidence: 89%

“…Some studies have not detected any differences (19,32), whereas others have reported an impact on negative selection (27,(33)(34)(35). CTLA-4 has also been suggested to affect thymic quantitative output of Foxp3 + Treg cells and to broaden the T-cell receptor (TCR) repertoire of Tconv cells in TCR transgenic mice specific for myelin basic protein (17,36). Taken together, the function of CTLA-4 is complex and likely operates by different mechanisms on different levels of tolerance via different cell populations.…”

Section: Foxp3mentioning

confidence: 99%

Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood

Klocke

Sakaguchi

Holmdahl

et al. 2016

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

182

132

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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4+Foxp3+ Treg cells. However, T cells from CTLA-4–deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4–deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.

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“…Moreover, there was an increase in the total number of Tregs and as a proportion of the total CD4+ cells in the lymph nodes, but not in the liver suggesting that the Tregs failed to migrate to the liver. Blockade of CTLA-4 signaling may interfere with the generation of both CD4+ and CD8+ T cells (47, 48), as well as the CD28-driven migration of memory T cells to extra-lymphoid tissue (49). Our findings support a similar regulation of migration of Tregs, thus explaining their failure to migrate to the liver.…”

Section: Discussionmentioning

confidence: 99%

Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy

Vudattu

Waldron‐Lynch

Truman

et al. 2014

The Journal of Immunology

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Immune deficient mice, reconstituted with human stem cells, have been used to analyze human immune responses in vivo. Although they have been used to study immune responses to xenografts, allografts, and pathogens, there have not been models of autoimmune disease in which the mechanisms of the pathologic process can be analyzed. We have found that reconstituted “humanized” mice treated with anti-CTLA-4 antibody (ipilimumab) develop autoimmune disease characterized by hepatitis, adrenalitis, sialitis, ANAs, and weight loss. Induction of autoimmunity involved activation of T cells and cytokine production and increased infiltration of antigen presenting cells. When anti-CTLA-4 mAb treated mice were co-treated with anti-CD3 mAb (teplizumab) hepatitis and ANAs were no longer seen and weight loss did not occur. The anti-CD3 blocked proliferation and activation of T cells, release of IFNγ and TNF, macrophage infiltration and release of IP-10 that was induced with anti-CTLA-4 mAb. We also found increased levels of Tregs (CD25+CD127-) in the spleen and mesenteric lymph nodes in the mice treated with both antibodies and greater constitutive phosphorylation of STAT5 in Tregs in spleen cells compared to mice treated with anti-CTLA-4 mAb alone. We describe the first model of human autoimmune disease in vivo. Humanized mice may be useful for understanding the mechanisms of biologics that are used in patients. Hepatitis, lymphadenopathy, and other inflammatory sequelae are side effects of ipilumimab treatment in humans and the present study may provide insights into this pathogenesis and the effects of immunologics on autoimmunity.

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CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Cited by 46 publications

References 60 publications

Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression

Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression

Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood

Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy

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