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T cell receptor signalling in the control of regulatory T cell differentiation andfunction
Ming O.Li1 and Alexander Y.Rudensky2
Abstract | Regulatory Tcells (TReg cells), a specialized Tcell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of Tcell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells.
Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease.
As a major tenet of modern immunology, Burnets clonal selection theory postulated that differentiating lymphocytes adopt distinct cell fates when they encounter foreign or self antigens in the primary lymphoid organs or peripheral tissues1. Whereas foreign antigens induce clonal expansion and effector differentiation of mature lymphocytes, self antigens were proposed to trigger clonal deletion of immature lymphocytes as a means to weed out potentially damaging autoreactive cells. Although the basic principles of the clonal selection theory have stood the test of time, both self antigens and foreign antigens are now known to also promote alternative Tcell fates, including the differentiation of thymus- derived regulatory
T cells (tTReg cells) and peripherally derived TReg cells (pTRegcells) (reviewed in REFS2,3).
Thymic escape of pathogenic self-reactive Tcells and the generation of TReg cells that can prevent disease were first revealed in neonatal thymectomy
studies thatwere performed half a century ago4. Subsequent efforts at identifying TReg cells that are capable of suppressing autoimmune inflammation revealed that they express high levels of Tcell receptor (TCR)-induced CD5, cytotoxic T lymphocyte antigen 4 (CTLA4) and CD25 (also known as IL-2R)57, and low expression of TCR-repressed CD45RB8,9. The subsequent identification of the Xchromosome- encoded transcription factor forkhead box P3 (FOXP3) as a dedicated TReg cell lineage specification factor enabled stringent characterization of TReg cell differentiation and function1012. Analysisof mice expressing a functional Foxp3 reporter or a reporter of a non-functional Foxp3 allele demonstrated a requirement for TCR signalling for FOXP3 expression and showed that TCR signalling precedes the induction of Foxp3 gene transcription1315. Notably, TCR stimulation not only activates transcriptional programmes
that are associated with TRegcell development, including the IB...