Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells

Garbi, Natalio; Hämmerling, Günter J.; Probst, Hans Christian; Broek, Maries van den

doi:10.1016/j.coi.2010.08.007

Cited by 42 publications

(42 citation statements)

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“…Over the past decade, it has become clear that steady-state DCs play an important role in the maintenance of self-tolerance (1-3) and T-cell responsiveness (4). Because DCs can either prime or tolerize naive T cells, depending on their activation status, they are master regulators of adaptive immunity.…”

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confidence: 99%

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Muth

Schütze

Schild

et al. 2012

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

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Resting dendritic cells (DCs) induce tolerance of peripheral T cells that have escaped thymic negative selection and thus contribute significantly to protection against autoimmunity. We recently showed that CD4 + Foxp3+ regulatory T cells (Tregs) are important for maintaining the steady-state phenotype of DCs and their tolerizing capacity in vivo. We now provide evidence that DC activation in the absence of Tregs is a direct consequence of missing DC-Treg interactions rather than being secondary to generalized autoimmunity in Treg-less mice. We show that DCs that lack MHC class II and thus cannot make cognate interactions with CD4 + T cells are completely unable to induce peripheral CD8 + T-cell tolerance. Consequently, mice in which interactions between DC and CD4 + T cells are not possible develop spontaneous and fatal cytotoxic T lymphocyte-mediated autoimmunity. DCs are bone marrow (BM)-derived, short-lived cells that play a key role in regulating immune responses. They are located at low frequency in lymphoid and nonlymphoid organs throughout the body, where they act as sentinels for invading pathogens. On recognition of pathogen-associated cues, DCs undergo a series of functional changes termed maturation, which is characterized by the up-regulation of costimulatory molecules such as CD80, CD86, and CD70, by the production of cytokines, such as IL-12, and by the expression of homing receptors, such as CCR7, that direct DC migration into the T-cell areas of secondary lymphoid organs. Together these changes allow DCs to efficiently activate naive T cells.Over the past decade, it has become clear that steady-state DCs play an important role in the maintenance of self-tolerance (1-3) and T-cell responsiveness (4). Because DCs can either prime or tolerize naive T cells, depending on their activation status, they are master regulators of adaptive immunity. How the maturation status of DCs translates into differential effects on naive T cells involves a variety of costimulatory and coinhibitory interactions between T cells and DCs. For example, we showed that tolerance induction depends on PD-1 and CTLA-4 (5), whereas blockade of CD70, a costimulatory molecule that is upregulated on activated DCs, prevents priming of CD8 + T cells even in the context of an infection (6). Along the same line, constitutive transgenic expression of CD70 on all DCs prevents the induction of tolerance and results in priming of a functional T-cell response by steady-state DCs (7).DC maturation can be triggered by numerous exogenous and endogenous stimuli that are usually associated with infection, inflammation, or damage (8 (10)(11)(12)(13)(14). Tregs may control self-reactive T-cell responses by direct interaction with conventional T cells or, alternatively, may act on DCs (15). Evidence for the latter comes from experiments in which depletion of Tregs results in Flt3-dependent increases in the number of DCs as well as in DC activation (9,11,16).When we combined the DIETER model of peripheral tolerance induction by steady-state DCs a...

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confidence: 99%

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Muth

Schütze

Schild

et al. 2012

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

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“…Thus, suppressor activity is not strictly correlated to Foxp3 expression level. One explanation could be that most T cells from Foxp3 transgenic mice are in fact naive T cells forced to express Foxp3, and that, as all naive T cells, they have only a limited affinity for self and subsequently receive only weak TCR signals.Interruption of Tconv-cell contact with self-peptide MHC ligands leads to a rapid decline on signaling and response sensitivity to foreign stimuli [23]. In the present article, we show that in contrast with Tconv cells, self-deprivation does not lead to a defect in Treg-cell ability to be activated by TCR signals.…”

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confidence: 47%

Foxp3‐independent loss of regulatory CD4⁺T‐cell suppressive capacities induced by self‐deprivation

et al. 2012

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In the periphery, Foxp3 expression is considered sufficient to maintain natural regulatory CD4 + T-cell suppressive function. In this study, we challenge this model. Indeed, in mouse chimeras in which major histocompatibility complex (MHC) class II expression is restricted to the thymus, peripheral regulatory CD4 + T cells lack suppressive activity. In addition, regulatory CD4 + T cells recovered 5 days after transfer into recipient mice lacking expression of MHC class II molecules (self-deprived) are unable to inhibit the proliferative response of conventional CD4 + T cells both in vitro and in vivo. Disruption of TCR/MHC class II interactions rapidly leads to alterations in the regulatory CD4 + T-cell phenotype, the ability to respond to stimulation and to produce interleukin-10, and the transcriptional signature. Interestingly, self-deprivation does not affect Foxp3 expression indicating that in regulatory CD4 + T cells, self-recognition induces unique transcriptional and functional features that do not rely on Foxp3 expression. Keywords: Autoreactivity r Foxp3 r Regulatory T cells Supporting Information available online IntroductionNaturally occurring regulatory CD4 + T (Treg) cells are important for the maintenance of self-tolerance in the periphery. In particular, they are key players in the prevention of various autoimmune and inflammatory disorders. Natural Treg cells arise in the thymus where T-cell receptor (TCR) signals lead to interleukin (IL)-2 sensitivity enhancement in developing thymocytes. Then, IL-2 signaling induces Foxp3 expression that, in turn, strengthens Treg-cell lineage stability [1,2]. Foxp3 expression is Correspondence: Dr. Bruno Lucas e-mail: bruno.lucas@inserm.fr then important to maintain a distinct transcriptional program required for their suppressive function [3][4][5].Recent studies have clearly established that the TCR has an instructive role in inducing commitment of developing thymocytes into the Treg-cell lineage [6,7]. More precisely, Treg-cell development would be instructed by TCRs with high avidity for self-peptides bound to major histocompatibility complex (MHC) class II molecules (self). Indeed, the proportion of Treg cells is increased when TCR transgenic T cells are forced to see their cognate antigens in the thymus [1,2,8,9]. This model is further supported by the observation that there is a limited amount of * These authors contributed equally to this work. overlap (10-20%) between the TCR sequences expressed within the conventional CD4 + T (Tconv) cell and the Treg-cell repertoire [10]. Interestingly, overlapping is more important when the Tregcell repertoire was compared with the repertoire of pathogenic autoreactive effector T cells [11]. After migrating to the periphery, Treg cells still interact with self. Indeed, based on autoimmune ovarian disease and prostatitis models, Tung and colleagues [12,13] have determined that continuous interactions with self are required to allow Treg cells to accumulate in the draining lymph-nodes. More recently, Lathrop et al. ...

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“…In such a hypothesis, antisynapses would contribute to the integration of TCR signals. Such putative nanoclusters could also be generated by self-recognition and underlie the tonic signaling phenomenon (Garbi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

T cell adhesion triggers an early signaling pole distal to the immune synapse

Guedj

Abraham

Jullié

et al. 2016

Journal of Cell Science

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The immunological synapse forms at the interface between a T cell and an antigen-presenting cell after foreign antigen recognition. The immunological synapse is considered to be the site where the signaling cascade leading to T lymphocyte activation is triggered. Here, we show that another signaling region can be detected before formation of the synapse at the opposite pole of the T cell. This structure appears during the first minute after the contact forms, is transient and contains all the classic components that have been previously described at the immunological synapse. Its formation is independent of antigen recognition but is driven by adhesion itself. It constitutes a reservoir of signaling molecules that are potentially ready to be sent to the immunological synapse through a microtubuledependent pathway. The antisynapse can thus be considered as a pre-synapse that is triggered independently of antigen recognition.

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Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells

Cited by 42 publications

References 62 publications

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Foxp3‐independent loss of regulatory CD4⁺T‐cell suppressive capacities induced by self‐deprivation

T cell adhesion triggers an early signaling pole distal to the immune synapse

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Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells

Cited by 42 publications

References 62 publications

Release of dendritic cells from cognate CD4+T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Release of dendritic cells from cognate CD4+T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Foxp3‐independent loss of regulatory CD4+T‐cell suppressive capacities induced by self‐deprivation

T cell adhesion triggers an early signaling pole distal to the immune synapse

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Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Foxp3‐independent loss of regulatory CD4⁺T‐cell suppressive capacities induced by self‐deprivation