From thymus to periphery: molecular basis of effector γδ‐T cell differentiation

H2020 European Research Council. Grant Number: CoG_676401. European Commission Marie Sklodowska‐Curie Individual Fellowship. Grant Number: 752932.The contributions of γδ T cells to immune (patho)physiology in many pre-clinical mouse models have been associated with their rapid and abundant provision of two critical cytokines, interferon-γ (IFN-γ) and interleukin-17A (IL-17). These are typically produced by distinct effector γδ T cell subsets that can be segregated on the basis of surface expression levels of receptors such as CD27, CD44, or CD45RB, among others. Unlike conventional T cells that egress the thymus as naïve lymphocytes awaiting further differentiation upon activation, a large fraction of murine γδ T cells commits to either IFN-γ or IL-17 expression during thymic development. However, extrathymic signals can both regulate pre-programmed γδ T cells; and induce peripheral differentiation of naïve γδ T cells into effectors. Here we review the key cellular events of "developmental pre-programming" in the mouse thymus; and the molecular basis for effector function maintenance vs plasticity in the periphery. We highlight some of our contributions towards elucidating the role of T cell receptor, co-receptors (like CD27 and CD28) and cytokine signals (such as IL-1β and IL-23) in these processes, and the various levels of gene regulation involved, from the chromatin landscape to microRNA-based post-transcriptional control of γδ T cell functional plasticity.