Innate acting memory Th1 cells modulate heterologous diseases

Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon rechallenge with the same pathogen, their impact on susceptibility to unrelated diseases is unclear. We identify a subset of memory T helper 1 (Th1) cells termed innate acting memory T (T_IA) cells that originate from a viral infection and produce IFN-γ with innate kinetics upon heterologous challenge in vivo. Activation of memory T_IA cells is induced in response to IL-12 in combination with IL-18 or IL-33 but is TCR independent. Rapid IFN-γ production by memory T_IA cells is protective in subsequent heterologous challenge with the bacterial pathogen Legionella pneumophila. In contrast, antigen-independent reactivation of CD4⁺ memory T_IA cells accelerates disease onset in an autoimmune model of multiple sclerosis. Our findings demonstrate that memory Th1 cells can acquire additional TCR-independent functionality to mount rapid, innate-like responses that modulate susceptibility to heterologous challenges.