Dissecting CD8⁺ NKT cell responses to listeria infection reveals a component of innate resistance

A small pool of NK1.1⁺ CD8⁺ T cells is harbored among the conventional CD8⁺ T cell compartment. Conclusions drawn from the analysis of immune responses mediated by cytotoxic CD8⁺ T cells are often based on the total population, which includes these contaminating NK1.1⁺ CD8⁺ T cells. An unresolved question is whether NK1.1⁺ CD8⁺ cells are conventional T cells that acquire NK1.1 expression upon activation or delineation into memory phenotype or whether they are a distinct cell population that induces immune responses in a different manner than conventional T cells. To address this question, we used the Listeria monocytogenes model of infection and followed CD8⁺ NK1.1⁺ T cells and NK1.1^- CD8⁺ T cells during each phase of the immune response: innate, effector, and memory. Our central finding is that CD8⁺ NK1.1⁺ cells and conventional NK1.1^- CD8⁺ T cells both contribute to the adaptive immune response to Listeria, but only CD8⁺ NK1.1⁺ cells were equipped with the ability to provide a rapid innate immune response, as demonstrated by early and Ag-independent IFN-γ production, granzyme B expression, and degranulation. More importantly, purified conventional CD8⁺ T cells alone, in the absence of any contaminating CD8⁺ NK1.1⁺ cells, were not sufficient to provide early protection to lethally infected mice. These results highlight the role of CD8⁺ NK1.1⁺ T cells in mounting early innate responses that are important for host defense and support the therapeutic potential of this subset to improve the effectiveness of protective immunity.