Regulatory T cells: mechanisms of differentiation and function

Abstract

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell-mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

Figure 1

TCR signal strength instructs CD4⁺ thymocyte fate and regulatory T cell differentiation. Immature CD4 single-positive (SP) thymocytes receive TCR signals of varied strength via interactions with peptide-MHC on antigen-presenting cells. The strength of TCR signals (or functional avidity, based on a composite of individual peptide-MHC-TCR interaction affinity and peptide-MHC abundance) and their duration determines CD4 SP thymocyte fate. Upon reception of a TCR signal of high strength, most CD4 SP thymocytes undergo programmed cell death. A number of CD4 SP thymocytes receiving TCR signals of intermediate strength are able to escape deletion and are enriched for cells that are instructed to differentiate into Foxp3⁺ Treg cells. Weight of arrows reflects relative probability of the indicated outcomes.

Figure 2

Regulatory T (Treg) cell heterogeneity and suppression of distinct classes of the immune response. Treg cells generated in the thymus or extrathymically can further specialize through upregulation or activation of transcription factors in response to different environmental stimuli. These environmental response factors can cooperate with Foxp3 to confer to Treg cells a transient or lasting cell state, enabling their tailored function under particular environmental or inflammatory conditions; for example, STAT3 activation in response to IL-10 leads to the generation of pSTAT3⁺ Treg cells capable of suppressing Th17 responses, or activation of STAT1 in response to IFN-γ or other STAT1-signaling cytokines leads to generation of Tbet⁺ Treg cells. In a given tissue, Treg cells, upon instruction by the tissue environment, induce expression of tissue-specific transcription factors whose cooperation with Foxp3 results in a distinct tissue-specific Treg cell transcriptional signature and function, and also supports Treg cell subset homeostasis.