T-cell receptor affinity in thymic development

Abstract

Understanding the thymic processes that support the generation of functionally competent and self-tolerant lymphocytes requires dissection of the T-cell receptor (TCR) response to ligands of different affinities. In spatially segregated regions of the thymus, with unique expression of proteases and cytokines, TCR affinity guides a number of cell fate decisions. Yet affinity alone does not explain the selection paradox. Increasing evidence suggests that the 'altered peptide' model of the 1980s together with the affinity model might best explain how the thymus supports conventional and regulatory T-cell development. Development of new tools to study the strength of TCR signals perceived by T cells, novel regulatory T-cell transgenic mice, and tetramer enrichment strategies have provided an insight into the nature of TCR signals perceived during thymocyte development. These topics are discussed and support for the prevailing hypotheses is presented.

Figure 1

Threshold versus sustained signalling models of thymic selection. (a) A simplistic model to explain how T-cell receptor (TCR) signal strength can influence positive/negative selection invokes a higher threshold for negative selection, and a lower threshold for positive selection. Clones with TCRs that recognize and transduce a signal sufficient to promote survival and differentiation but not strong enough to trigger apoptosis are positively selected by the process. Importantly, in this model if apoptosis were prevented, high-affinity interactions would lead to positive selection. (b) Evidence suggests that stronger proximal TCR signals induce more negative feedback. A sustained signalling model proposes that low-affinity TCR interactions trigger positive selection because they are sustained over time. High-affinity signals can trigger apoptosis. However, in this model if apoptosis were prevented, high-affinity interactions would still not lead to positive selection because of the lack of a sustained TCR signal.

Figure 2

T regulatory (Treg) cells integrate cytokine and antigen receptor signal strength cues during thymic development. CD4⁺ CD8⁺ double-positive (DP) thymocytes undergo positive selection on cortical thymic epithelial cells (cTECs) presenting low-affinity peptide–MHC complex (pMHC) ligands in the thymic cortex, then migrate to the medulla where they encounter novel pMHC ligands on medullary thymic epithelial cells (mTECs) and dendritic cells. Those clones that encounter high-affinity pMHC ligands will be triggered to undergo apoptosis. However, clones that coincidently encounter survival cytokines such as interleukin-2 (IL-2) or transforming growth factor β (TGFβ), could be rescued and directed to become a Treg cell. Such clones would express TCRs unique to the Treg-cell population. Clones with a slightly lower relative affinity (medium) could either develop into a conventional CD4⁺ T cell in the absence of a cytokine encounter, or into a regulatory T cell with exposure to IL-2. Hence, some TCRs in the Treg-cell repertoire would overlap with those of conventional CD4⁺ T cells.