BATF represses BIM to sustain tolerant T cells in the periphery.

T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to proapoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM derepression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.

VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance.

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

Anergy into T regulatory cells: an integration of metabolic cues and epigenetic changes at the Foxp3 conserved non-coding sequence 2.

Peripheral immune self-tolerance relies on protective mechanisms to control autoreactive T cells that escape deletion in the thymus. Suppression of autoreactive lymphocytes is necessary to avoid autoimmunity and immune cell-mediated damage of healthy tissues. An intriguing relationship has emerged between two mechanisms of peripheral tolerance-induction of anergy and Foxp3 + regulatory T (Treg) cells-and is not yet well understood. A subpopulation of autoreactive anergic CD4 T cells is a precursor of Treg cells. We now hypothesize that phenotypic and mechanistic features of Treg cells can provide insights to understand the mechanisms behind anergy-derived Treg cell differentiation. In this short review, we will highlight several inherent similarities between the anergic state in conventional CD4 T cells as compared with fully differentiated natural Foxp3 + Treg cells and then propose a model whereby modulations in metabolic programming lead to changes in DNA methylation at the Foxp3 locus to allow Foxp3 expression following the reversal of anergy.