Interleukin-1 and IL-23 Induce Innate IL-17 Production from γδ T Cells, Amplifying Th17 Responses and Autoimmunity

Abstract

Th17 cells, CD4(+) T cells that secrete interleukin-17 (IL-17), are pathogenic in autoimmune diseases and their development and expansion is driven by the cytokines IL-6, TGF-beta, IL-21, IL-1, and IL-23. However, there are also innate sources of IL-17. Here, we show that gammadelta T cells express IL-23R and the transcription factor RORgammat and produce IL-17, IL-21, and IL-22 in response to IL-1beta and IL-23, without T cell receptor engagement. IL-17-producing gammadelta T cells were found at high frequency in the brain of mice with experimental autoimmune encephalomyelitis (EAE). gammadelta T cells activated by IL-1beta and IL-23 promoted IL-17 production by CD4(+) T cells and increased susceptibility to EAE, suggesting that gammadelta T cells act in an amplification loop for IL-17 production by Th17 cells. Our findings demonstrate that gammadelta T cells activated by IL-1beta and IL-23 are an important source of innate IL-17 and IL-21 and provide an alternative mechanism whereby IL-1 and IL-23 may mediate autoimmune inflammation.

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

“…γδ 17 cells are functionally committed in the thymus, producing IL‐17 in the periphery after stimulation with IL‐1 β and IL‐23 without additional TCR stimulation 21, 24. The ‘ready‐to‐go’ phenotype of γδ 17 cells is especially efficient for early‐stage pathogen clearance.…”

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

“…Early reports by Lochner et al suggested that the mechanism of γδ17 programming differed from that of Th17, as it did not rely on IL-6 17 . Noting the relevance of IL-23 in γδ17 mediated autoimmune pathogenesis, Sutton and colleagues demonstrated that IL-1β and IL-23 could induce the production of IL-17 by innate-like γδ T cells in the periphery 18 . However, other reports have shown that IL-17 production by γδ T cells in the intestinal mucosa is IL-23 independent, despite these cells being IL-23R + 8 .…”

γδ-T cells: an unpolished sword in human anti-infection immunity

“…111 The contribution of cd-T cells to adaptive immunity goes beyond their APC function mentioned above. For example, cd-T cells are capable of inducing the maturation of DCs, 67 facilitating the development of ab-T cells, 13,112 killing regulatory T cells (Tregs) 113,114 and migrating into the secondary lymphoid tissues and acting as follicular B helper T cells to promote antibody production. 115,116 Moreover, cd-T cells can compete with ab-T cells for growth factors such as IL-15 and thus modify the adaptive immune response.…”

“…154,155 The major concern with using cd-T cell-based anti-infection therapy comes from its pro-inflammatory characteristics. These potential risks might be induced by overdoses or bystander effects and result in cd-T cell-triggered autoimmune diseases 13 or general inflammatory diseases. 156 It has been shown that one auto-aggressive cd-T-cell subset recognizing aminoacyl-tRNA synthetases that are shared by bacteria and humans can be detected in some myositis patients and might contribute to the pathogenesis of their disease.…”

“…2 On the one hand, epidermal cd-T cells play an indispensable role in limiting and eliminating invasive pathogens and recruiting inflammatory cells to infected locations, 6,7 while skin cd-T cells promote tissue repair by producing keratinocyte growth factor. 8 On the other hand, some cd-T cells, especially IL-17-producing cd-T cells, have been confirmed to be involved in the pathogenesis of transplantation rejection, 9 autoimmune diseases, [10][11][12][13] inflammatory diseases 14,15 and allergy 16 in human and animal models. However, the scarcity of peripheral cd-T cells and the difficulties in monitoring their fate in vivo make it difficult to achieve a comprehensive understanding of the characteristics of human cd-T cells.…”