IL-4 sensitivity shapes the peripheral CD8⁺ T cell pool and response to infection

Previous studies have revealed that a population of innate memory CD8⁺ T cells is generated in response to IL-4, first appearing in the thymus and bearing high expression levels of Eomesodermin (Eomes) but not T-bet. However, the antigen specificity and functional properties of these cells is poorly defined. In this study, we show that IL-4 regulates not only the frequency and function of innate memory CD8⁺ T cells, but also regulates Eomes expression levels and functional reactivity of naive CD8⁺ T cells. Lack of IL-4 responsiveness attenuates the capacity of CD8⁺ T cells to mount a robust response to lymphocytic choriomeningitis virus infection, with both quantitative and qualitative effects on effector and memory antigen-specific CD8⁺ T cells. Unexpectedly, we found that, although numerically rare, memory phenotype CD8⁺ T cells in IL-4Rα-deficient mice exhibited enhanced reactivity after in vitro and in vivo stimulation. Importantly, our data revealed that these effects of IL-4 exposure occur before, not during, infection. Together, these data show that IL-4 influences the entire peripheral CD8⁺ T cell pool, influencing expression of T-box transcription factors, functional reactivity, and the capacity to respond to infection. These findings indicate that IL-4, a canonical Th2 cell cytokine, can sometimes promote rather than impair Th1 cell-type immune responses.