Exhausted CD8 T cells become unresponsive to activation by innate cytokines and bystander bacterial infections (45.12)

Abstract

Abstract During many chronic infections T cell responses initially develop, but succumb to exhaustion, as they lose their ability to produce interferon-γ (IFNγ) in response to antigen. Combinations of interleukins (IL)- 12, 18, and 21 have been shown to induce the antigen-independent production of IFNγ by prototypic memory CD8 T cells; therefore, we evaluated the sensitivity of exhausted lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells to activation with these cytokines. Our findings show that following acute infection, effector CD8 T cells respond synergistically to stimulation by these cytokines, but this responsiveness is abolished in exhausted T cells. To evaluate mechanisms responsible for this loss of responsiveness, we examined the expression of the cognate cytokine receptors. Whereas effector and memory T cells express the IL-18R, exhausted T cells downregulated the IL-18R but expressed higher levels of the IL-21R. To evaluate the biological consequences of this decreased sensitivity, we challenged cohorts of LCMV infected mice with the intracellular bacterial pathogen Listeria. Although LCMV-specific memory CD8 T cells vigorously respond to the bacterial infection, this responsiveness is severely compromised during protracted or chronic LCMV infections. Collectively, our findings show that exhausted cells downregulate IL-18R and become desensitized to activation by innate cytokines, rendering them unresponsive to secondary bacterial infections.