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

The contributions of gamma delta 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-gamma (IFN-gamma) and interleukin-17A (IL-17). These are typically produced by distinct effector gamma delta 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 naive lymphocytes awaiting further differentiation upon activation, a large fraction of murine gamma delta T cells commits to either IFN-gamma or IL-17 expression during thymic development. However, extrathymic signals can both regulate pre-programmed gamma delta T cells; and induce peripheral differentiation of naive gamma delta 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-1 beta 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 gamma delta T cell functional plasticity.