TCR signals fuel Treg cells

Regulatory T (T reg) cells safeguard against autoimmunity and overshooting inflammation. During their development in the thymus, T reg cells are selected by stronger autoantigenic T cell receptor (TCR) signals than conventional T cells. These TCR signals are critically important for the initiation of two key lineage defining events, namely induction of the transcription factor Foxp3 and hypomethylation of a specific gene set. Recent studies shed light on the role of continuous (autoreactive) TCR signals for identity, homeostasis and functions of mature T reg cells. Induced TCR ablation on mature T reg cells only minimally reduces Foxp3 expression [1, 2] and does not affect hypomethylation patterns [1]. Stable Foxp3 expression was also observed in T reg cells lacking the TCR signal transduction proteins Lck [3] or SLP-76 [4] and upon ablation of the co-stimulatory receptor CD28 [5]. Fittingly, mature T reg cells, expressing a TCR but deprived of peripheral autoantigenic stimulation due to lack of MHC II on hematopoietic cells, still express Foxp3 [6]. Therefore, once a core T reg cell identity has been established in the thymus, it is maintained independently of peripheral TCR signals. In contrast, the T reg cell surface phenotype and their signature gene expression were strongly affected by the various means of inhibiting TCR signals [1-3, 6]. However, the peripheral T reg cell pool is heterogeneous in that it consists of naïve and various subsets of effector-like T reg cells. Induced TCR ablation showed that, at least under homeostatic conditions in healthy mice, effector-like T reg cells strictly depend on TCR signals for their generation and/or maintenance. Attempts to distinguish between naïve and effector-like T reg cells based on CD62L/CD44 [2] or CD25 [1] expression revealed that both require TCR signals to maintain their characteristic surface phenotype and gene expression, independently of their homeostasis. Interestingly, apart from reduced levels of TCR-activated transcription factors such as Egr2 and c-Rel and their respective target genes, loss of TCR signals strongly affects IRF4-controlled genes. The concept that DNA hypomethylation ensures the expression of key T reg cell genes is supported by the reduced, but still robust expression of CTLA-4, GITR and Eos of TCR-deficient T reg cells [1]. Both induced TCR and co-stimulatory CD28 ablation cause a decline in T reg cells in the absence of thymic T cell production, which goes hand in hand with completely abrogated [1] or reduced [5] homeostatic proliferation, respectively. This is not …