Interleukin-1 and IL-23 induce innate-like immune responses by bystander-activated memory CD4+ T cells contributing to the autoimmune pathogenesis

Abstract

Abstract Antigen-nonspecific bystander activation of CD4+ T lymphocytes have been recently discovered. However, the immunopathological role of non-specific bystander activated CD4+ T cells responding to pro-inflammatory cytokines remains unknown. Here, we show that IL-1β acted directly on polyclonal memory, but not naïve, CD4+ T cells in synergy with IL-23 to promote IL-17A and IFN-γ expression in both mice and human. This bystander CD4+ T cell activation is dependent on IL-1 but not T cell antigen receptors (TCRs). In vivo, co-transfer of MOG-specific TCR transgenic (2D2) naïve T cells with MOG-nonspecific TCR transgenic (OT-II) memory-like Th17 cells increased susceptibility to EAE. IL-1 dependent MOG-nonspecific memory-like Th17 cells infiltrated to the CNS producing IL-17A, IFN-γ, and GM-CSF, which made important contributions to the development of autoimmune neuroinflammation. Our findings demonstrate that IL-1β and IL-23 activates TCR-independent innate-like immune responses by bystander activated memory CD4+ T cells contributing to the autoimmune disease pathogenesis.