Upon activation, naive CD4 T cells differentiate into a variety of T-helper-cell subsets characterized by different cytokine production and functions. Currently, lineage commitment is considered to depend mostly on the environmental context to which naive CD4 T cells are exposed. Here we challenge this model based on the supposed homogeneity of the naive CD4 T-cell compartment. We show that peripheral naive CD4 T cells can be subdivided into two subsets according to Ly-6C expression. Furthermore, the two newly defined subsets (Ly-6C À and Ly-6C þ naive CD4 T cells) are not equal in their intrinsic ability to commit into the induced regulatory T-cell lineage. Finally, phenotypic analysis, imaging and adoptive transfer experiments reveal that Ly-6C expression is modulated by self-recognition, allowing the dichotomization of the naive CD4 T-cell compartment into two cell subsets with distinct self-reactivity. Altogether, our results show that naive CD4 T cells with the highest avidity for self are prone to differentiate into regulatory T cells.
CD4 regulatory T cells (Tregs) can be subdivided into two subsets according to Ly-6C expression in the periphery. Phenotypic analysis, imaging, and adoptive-transfer experiments of peripheral Ly-6C(-) and Ly-6C(+) Tregs reveal that the nonexpression of Ly-6C by ∼70% of peripheral Tregs depends on TCR signaling events. Interestingly, Ly-6C(-) Tregs express higher surface amounts of key immunosuppressive molecules than do Ly-6C(+) Tregs and produce constitutively anti-inflammatory cytokines. In line with their phenotype, Ly-6C(+) Tregs exhibit poor suppressive capacities in vitro and in vivo. Finally, although Ly-6C(-) Tregs maintain their numbers with age, Ly-6C(+) Tregs gradually disappear. Altogether, our data strongly suggest that both the survival and suppressive functions of peripheral CD4 Tregs rely on their ability to receive strong TCR signals.
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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