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

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.