Steady-state memory-phenotype conventional CD4+ T cells exacerbating autoimmune neuroinflammation in bystander manner via Bhlhe40/GM-CSF axis

Abstract

Abstract Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, and their immunologic functions in autoimmune disease have not yet been studied. In this work, we unveil a unique phenotype of MP CD4+ T cells by analyzing single-cell transcriptomics and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells exist regardless of germ and food-antigen which are composed of heterogenous effector subpopulations. Distinct subpopulations of MP CD4+ T cells are specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells have TCR-independent bystander effector functions like innate lymphoid cell. Especially, CCR6high MP CD4+ T cells are major responders to IL-1β and IL-23 without MOG35 − 55 antigen reactivity, which gives them pathogenic-Th17 characteristics and allows them to contribute to autoimmune encephalomyelitis. We identified Bhlhe40 in CCR6high MP CD4+ T cells drives the expression of GM-CSF through IL-1β and IL-23 signaling, contributing to CNS pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal clearly distinct effector-like heterogeneity of MP CD4+ T cells in steady state and CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation by Bhlhe40/GM-CSF axis in bystander manner synergistically with antigen-specific T cells.