Expression of the transcription factor Helios identifies thymocyte divergence during positive and negative selection.

T cell discrimination of self and non-self is predicated on αβ T cell receptor (TCR) co-recognition of peptides presented by MHC molecules. Over the past 20 years, structurally focused investigations into this MHC-restricted response have provided profound insights into T cell function. Simultaneously, two models of TCR recognition have emerged, centred on whether the TCR has, through evolution, acquired an intrinsic germline-encoded capacity for MHC recognition or whether MHC reactivity is conferred by developmental selection of TCRs. Here, we review the structural and functional data that pertain to these theories of TCR recognition, which indicate that it will be necessary to assimilate features of both models to fully account for the molecular drivers of this evolutionarily ancient interaction between the TCR and MHC molecules.

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing–based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 “mature” MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ–producing MAIT1 cells and interleukin-17–producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)–deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

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