research HIGHLIGHTS

AUTOIMMUNITY IL-17A brings new recruits to EAE IL-17A and IL-17A-producing​ significantly reduced in the lymph Furthermore, treatment with T cells are key mediators of various nodes of Il17a–/– mice compared antibody to IL-1β during EAE IL-17A pro­ autoimmune diseases, including with wild-​type mice immunized with induction in wild-type​ mice reduced duced by . Generally, IL-17A MOG plus adjuvant, and the Il17a–/– the severity of disease, which was produced by autoantigen-specific​ CD4+ T cells had reduced expression associated with reduced activation of antigen-​ CD4+ T cells in the diseased tissue is of the integrin VLA4, which drives MOG-​specific T cells in the lymph nonspecific thought to promote the production of infiltration of the CNS. nodes. Together, the results suggest γδ T cells in inflammatory mediators by epithelial In a transfer model, donor T cells that the role of IL-17A in disease the periphery cells. However, new findings from MOG-immunized​ wild-type​ or induction involves promoting published in Immunity suggest that, Il17a–/– mice were expanded in vitro, IL-1β production to activate recruits innate in a mouse model of T cell-driven​ with MOG alone or with MOG plus encephalitogenic T cells. immune cells central nervous system (CNS) IL-1β and IL-23, then transferred In looking for the cellular that prime , IL-17A produced by into naive wild-type​ mice. Both source of this IL-17A-induced​ –/– pathogenic antigen-nonspecific​ γδ T cells in the wild-​type and Il17a T cells induced IL-1β production, they found high periphery recruits innate immune severe EAE in recipient mice after levels of expression of IL-17RA T cells cells that prime pathogenic T cells. culture with MOG, IL-1β and IL-23, on neutrophils and Ly6Chi First, McGinley et al. showed which supports the hypothesis that inflammatory monocytes early in that, as expected, Il17a–/– mice are IL-17A production by T cells is not EAE. Il17a–/– mice had reduced resistant to the induction of myelin required for the effector phase of numbers of neutrophils and Ly6Chi oligodendrocyte glycoprotein disease, provided that polarizing monocytes in the spleen after (MOG)-induced experimental such as IL-1β are provided EAE induction. However, genetic autoimmune encephalomyelitis during the induction phase. The ablation of IL-17RA in myeloid (EAE), which correlated with a authors identified Vγ4+ γδ T cells, cells did not render mice resistant reduced number of pathogenic which can be activated by IL-1β and to EAE induction, which suggests T cells in the CNS. However, IL-23 independently of antigen, that IL-17A acts on non-myeloid​ treatment of mice with a neutralizing as an important cellular source cells to recruit the myeloid cells that antibody to IL-17A during the of IL-17A during this induction produce IL-1β. Further experiments effector phase of EAE did not affect phase of EAE. completed the missing details by disease severity. By contrast, antibody In keeping with the inductive showing that epithelial cells produce treatment during the induction role of IL-1β and IL-23 shown in the such as CXCL1 and phase delayed the onset of EAE and transfer model, the authors proposed CXCL2 in response to IL-17A, which attenuated symptoms, which was that IL-17A might be required for in turn recruit IL-1β-producing​ associated with reduced numbers early production of IL-1β and/or neutrophils and monocytes. of pathogenic T cells in the spleen. IL-23. They found significantly Thus, the results suggest a Thus, IL-17A seems to have an early reduced expression of Il1b in the positive-​feedback loop during role in the peripheral activation of lymph nodes of Il17a–/– mice, and EAE induction whereby IL-17A T cells that later infiltrate the CNS. administration of IL-1β to Il17a–/– production, mainly by γδ T cells, Indeed, the frequencies of -​ mice during EAE induction restored indirectly induces the recruitment producing CD4+ and γδ T cells were disease susceptibility. of myeloid cells that produce IL-1β, which in turn can synergise with IL-23 to activate γδ T cells and later CD4+ T cells that mediate the effector phase of disease.

Kirsty Minton

Original article McGinley, A. M. et al. -17A serves a priming role in autoimmunity by recruiting IL-1β-producing myeloid cells that promote pathogenic T cells. Immunity https://doi.org/10.1016/j.immuni. 2020.01.002 (2020) Credit: S. Bradbrook/Springer Nature Limited Nature Bradbrook/Springer S. Credit:

NAtuRe Reviews | ImmunoLogy volume 20 | MARCH 2020 | 137