Memory CD4 T cells help adaptive immunity with minimal immunopathology

CD4 T cells play critical roles in promoting inflammation and helping immune responses, but knowledge of how memory CD4 T cells are regulated and how they help adaptive immune responses is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that nave CD4 T cells undergo substantial expansion following viral infection, but can induce lethal TH1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper (Tfh) cell subsets that correlate with improved adaptive responses and minimal tissue damage following viral infection. Importantly, our analyses revealed that type I interferon regulates the expansion of nave CD4 T cells, but does not seem to play a critical role in regulating the expansion of memory CD4 T cells. Moreover, blockade of type I interferon signaling abrogated lethal CD4 T cell inflammation following viral infection. Taken together, these data demonstrate a previously undescribed function for memory CD4 T cells: to help adaptive immunity with minimal harm to the host. These findings are important for rational vaccine design and for improving the safety and efficacy of adoptive T cell therapies against persistent antigens.

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