Clonal deletion and the fate of autoreactive thymocytes that survive negative selection

Pobezinsky, Leonid A; Angelov, Georgi S.; Tai, Xuguang; Jeurling, Susanna; Laethem, François Van; Feigenbaum, Lionel; Park, Jung Hyun; Singer, Alfred

doi:10.1038/ni.2292

Cited by 148 publications

(188 citation statements)

References 51 publications

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“…Forced expression of full length or tailless CTLA-4 and resulting reduction of CD28 signaling skewed the TCR repertoire of developing Foxp3 − Tconv cells toward higher selfreactivity without significantly affecting their cell number (29,52,53). In line with this finding, the TCR repertoire of CD28-deficient Tconv cells was reported to be slightly more selfreactive than WT Tconv cells (29,52,53). On the other hand, Treg-specific CTLA-4 deficiency cancelled physiological selfskewing of their TCR repertoire.…”

Section: Discussionsupporting

confidence: 72%

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: Discussionsupporting

confidence: 72%

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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“…In accordance, a recent study confirmed the relevance of CD28 costimulation for clonal deletion of thymocytes in vivo (41). It is intriguing to speculate whether related mechanisms are also involved in the pathogenesis of chronic inflammatory neuropathies in humans.…”

Section: Discussionsupporting

confidence: 63%

Thymic Epithelium Determines a Spontaneous Chronic Neuritis in Icam1tm1JcgrNOD Mice

Hörste

Mausberg

Cordes

et al. 2014

The Journal of Immunology

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The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4+ T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1tm1JcgrNOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17–producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1tm1JcgrNOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1tm1JcgrNOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.

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“…The development of these innate-like T cells is thought to occur both in and outside the thymus, and also appears to be driven by high-affinity TCR interactions with their selection ligands (Pobezinsky et al 2012). In the absence of TGF-b signaling, the CD8aa þ TCRab þ IEL population is decreased, which is partially driven by a reduction in numbers of thymic precursors of these innate-like T cells (Konkel et al 2011).…”

Section: Tgf-b In the Immune System T Cellsmentioning

confidence: 99%

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Sanjabi

2017

Cold Spring Harb Perspect Biol

410

260

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Transforming growth factor b (TGF-b) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-b alters immunity under various conditions. Under steady-state conditions, TGF-b regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-b inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral ( p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-b controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-b plays a pivotal role in maintaining peripheral tolerance against self-and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

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Clonal deletion and the fate of autoreactive thymocytes that survive negative selection

Cited by 148 publications

References 51 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

Thymic Epithelium Determines a Spontaneous Chronic Neuritis in Icam1tm1JcgrNOD Mice

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

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