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,
CCR6 high 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 CCR6 high MP CD4T 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 CCR6 high MP CD4 T cells exacerbate autoimmune neuroinflammation by
Bhlhe40/GM-CSF axis in bystander manner synergistically with antigen-specific T cells.