Interleukin-17-producing γδ T (γδ17) cells in inflammatory diseases

Abstract

Interleukin-17 (IL-17) is a pro-inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL-17-producing γδ T cells (γδ17 cells) in addition to IL-17-producing CD4⁺ T cells [T helper type 17 (Th17) cells] are often the main producers of IL-17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra-thymic differentiation. γδ thymocytes capable of producing IL-17, which express the transcription factor retinoic-acid-receptor-related orphan receptor γt and the signature cytokine receptor IL-23R, leave the thymus, and produce IL-17 rapidly by the stimulation with IL-1β and IL-23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL-17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL-17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL-17.

Keywords: cytokines; inflammatory disease; pathogen clearance.

Figure 1

Distinct features of γδ17 cell subset and suggested model of ‘natural’ γδ17 cells versus ‘inducible’ γδ17 cells. Vγ6⁺ γδ T cells express the invariant Vγ6/Vδ1 T‐cell receptor (TCR), develop only in the late embryonic thymus, and preferentially localize to the uterus, vagina, lung, dermis and peritoneal cavity. On the other hand, Vγ4⁺ γδ T cells develop in both fetal and adult thymus and have a more diverse TCR repertoire. These cells circulate in blood and reside in the dermis, lung, liver and secondary lymphoid organs. In according to Haas et al.50 ‘natural’ γδ17 cells (Vγ6⁺ and part of Vγ4⁺) developed before birth acquire interleukin‐17 (IL‐17) ‐producing ability in thymus and produce IL‐17 stimulated by IL‐1β and IL‐23 in the periphery. Conversely, IL‐17 production induced by TCR signalling was also reported.56 Naive γδ T cells developed after birth may egress the thymus as ‘inducible’ γδ17 cells (mostly Vγ4⁺) and differentiate to produce IL‐17 after encounter with antigen.

Figure 2

Characterization of γδ17cells. γδ17 cells have some distinct phenotypes and are distinguished from interferon‐γ (IFN‐γ)‐producing γδ T cells ; γδ17 cells express interleukin‐1 receptor (IL‐1R), IL‐23R, IL‐7R, CCR2, CCR6, CD44 and Scart2 on the cell surface. The transcriptional factors of RORγt, Blk, Hes‐1, NF‐κB, Sox4 and Sox13 are important for γδ17 development. On the other hand, IFN‐γ‐producing γδ T cells express CD27, CD122 and NK1.1. These phenotypes are established during thymic development.