Abstract Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon re-challenge 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 re-activation 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.
