The T-cell receptor repertoire of regulatory T cells

Abstract

The CD4(+) CD25(+) regulatory population of T cells (Treg cells), which expresses the forkhead family transcription factor (Foxp3), is the key component of the peripheral tolerance mechanism that protects us from a variety of autoimmune diseases. Experimental evidence shows that Treg cells recognize a wide range of antigenic specificities with increased reactivity to self antigens, although the affinity of these interactions remains to be further defined. The Treg repertoire is highly diverse with a distinct set of T-cell receptors (TCRs), and yet is overlapping to some extent with the repertoire of conventional T cells (Tconv cells). The majority of Treg cells are generated in the thymus. However, the role of the TCR specificity in directing thymic precursors to become Treg or Tconv cells remains unclear. On the one hand, the higher self reactivity of Treg cells and utilization of different TCRs in Treg and Tconv repertoires suggest that in TCR interactions an initial decision is made about the 'suitability' of a developing thymocyte to become a Treg cell. On the other hand, as Treg cells can recognize a wide range of foreign antigens, have a diverse TCR repertoire, and show some degree of overlap with Tconv cells, the signals through the TCR may be complementary to the TCR-independent process that generates precursors of Treg cells. In this review, we discuss how different features of the Treg repertoire influence our understanding of Treg specificities and the role of self reactivity in the generation of this population.

Figure 1

Generation of specificities of the regulatory T (Treg) repertoire. (a) Commitment of Treg cells is driven by higher affinity interactions between the T-cell receptor (TCR) and major histocompatibility complex (MHC)/self-peptide complexes. These interactions induce the Treg phenotype and forkhead family transcription factor (Foxp3) expression and skew the specificity of the TCR repertoire towards self antigens. Consequently, conventional T cells (Tconv cells) and Treg cells express different sets of TCRs that recognize non-self or self antigens, respectively. The size of the sets of cognate specificities represents a number of different specificities, not the total number of cells. The distribution of TCR specificities does not account for the clonal frequency of individual specificities. (b) Currently unknown mechanisms generate precursors of Treg cells prior to the TCR selection. Treg precursors are subjected to TCR-dependent and -independent signals. Positive selection of both lineages proceeds on the same pool of self ligands testing the unbiased distribution of TCRs. Both Tconv and Treg repertoires have cognate specificities primarily directed to recognition of non-self antigens with small fractions of high-affinity self-reactive TCRs. (c) The functional status of pre-Treg cells allows a separation of TCRs between Tconv and Treg cells in combination with different accessory signals [interleukin (IL)-2/IL-2R, CD28/B7, CD40/CD40L and antigen-presenting cell (APC) types].