Innately versatile: γδ17 T cells in inflammatory and autoimmune diseases

IL-17-producing gamma delta (gamma delta 17) T cells form a versatile subset of cells that respond rapidly to innate stimuli and support the pro-inflammatory functions of different myeloid and lymphoid lineages, being particularly critical in the early stages of inflammatory and autoimmune responses. In mice, under homeostatic conditions, these innate-like lymphocytes are pre-programmed in the fetal thymus, through an intricate process involving both T cell receptor-dependent and -independent signals, which allows them to readily produce IL-17 upon stimulation. However, given their transcriptional and epigenetic wiring, gamma delta 17 T cells are permissive to different environmental instructions, and can readily acquire the ability to co-produce multiple cytokines, such as IFN-gamma, IL-22 and GM-CSF, that further propagate inflammation. Moreover, strong IL-23 signals, which are abundantly found in autoinflammatory conditions, are able to induce de novo differentiation of gamma delta 17 T cells from uncommitted precursors, both in mice and humans. This notwithstanding, the exact mechanisms responsible for gamma delta 17 T cell pathogenicity and multifunctionality are still poorly understood, especially in humans. The pathogenic roles attributed to gamma delta 17 T cells in autoimmune diseases stem mainly from their ability to recruit different inflammatory myeloid populations to the target tissue, and to modulate alpha beta T cell function, either by enhancing inflammatory T(H)17 responses, or by restraining regulatory T-reg cell activity. Given their capacity to link key inflammatory axes of innate and adaptive immunity, a better understanding of the molecular basis underpinning gamma delta 17 T cell plasticity, and how much this feature accounts for their pathophysiological roles, may be critical for developing novel therapeutic approaches. In this review, we discuss the importance of gamma delta 17 T cells in breaking tolerance and enhancing inflammation in various autoimmune diseases, such as multiple sclerosis, psoriasis and rheumatoid arthritis under the light of their basic biological traits, e.g. development, activation, effector functions and plasticity. (C) 2017 The Authors. Published by Elsevier Ltd.