Mucosal‐associated invariant T (MAIT) cells constitute a major fraction of innate‐like T cells in humans with critical roles in defense against microbial pathogens and in maintaining mucosal integrity. However, the molecular mechanisms underlying MAIT cell development remain largely elusive. Here we investigated the role of miR‐181a/b‐1, a pair of microRNAs that serve as rheostat of TCR signal strength, in this process. Loss of miR‐181a/b‐1 in mice resulted in a profound arrest in early MAIT cell development. As a consequence, in the absence of miR‐181a/b‐1, thymic MAIT cells failed to acquire functional maturity based on expression of transcription factors PLZF, T‐bet and RORγt. Temporal analysis of development using a molecular timer in combination with loss of miR‐181a/b‐1 revealed that MAIT cells complete functional maturation in the periphery and indicates that functionally mature MAIT cells in the thymus are long‐term resident cells. Thus, our study provides insight into the dynamics of MAIT cell development in vivo. Of note, deletion of miR‐181a/b‐1 alone completely mirrored loss of all miRNAs.

The selection of T cells during intra-thymic d evelopment is crucial to obtain a functional and simultaneously not self-reactive peripheral T cell repertoire. However, selection is a complex process dependent on T cell receptor (TCR) thresholds that remain incompletely understood. In peripheral T cells, activation, clonal expansion, and contraction of the active T cell pool, as well as other processes depend on TCR signal strength. Members of the microRNA (miRNA) miR-181 family have been shown to be dynamically regulated during T cell development as well as dependent on the activation stage of T cells. Indeed, it has been shown that expression of miR-181a leads to the downregulation of multiple phosphatases, implicating miR-181a as ‘‘rheostat’’ of TCR signaling. Consistently, genetic models have revealed an essential role of miR-181a/b-1 for the generation of unconventional T cells as well as a function in tuning TCR sensitivity in peripheral T cells during aging. Here, we review these broad roles of miR-181 family members in T cell function via modulating TCR signal strength.

Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known on how stage-specific alterations in cell-cycle behavior drive proliferation dynamics during T-cell development. Here, we employed in vivo dual-nucleoside pulse labeling combined with determination of DNA replication over time as well as fluorescent ubiquitination-based cell-cycle indicator mice to establish a quantitative high-resolution map of cell-cycle kinetics of thymocytes. We developed an agent-based mathematical model of T-cell developmental dynamics. To generate the capacity for proliferative bursts, cell-cycle acceleration followed a 'stretch model', characterized by simultaneous and proportional contraction of both G1 and S phase. Analysis of cell-cycle phase dynamics during regeneration showed tailored adjustments of cell-cycle phase dynamics. Taken together, our results highlight intrathymic cell-cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T-cell developmental program.