Chronic viral infection: the perfidious role of IL-2 and IL-15 on CD8 T cell exhaustion (IRM4P.500)

Abstract

Abstract CD8 T cell exhaustion is a major immuno-regulatory mechanism by which chronic viruses escape the immune response. However, little is known on the factors regulating the unresponsiveness of CD8 T cells is this context. Here, we investigated the combined role of IL-2 and IL-15, two common gamma chain-dependent cytokines, on CD8 T cell differentiation and exhaustion during a chronic viral infection. We performed adoptive transfer of WT or IL-2RβKO P14 CD8 T cells (unresponsive to both IL-2 and IL-15 signals) in mice challenged with LCMV clone 13. Initially, IL-2Rβ-signals were critical for short-lived effector cell differentiation. IL-2 and IL-15 conditioned optimal proliferation of early effector CD8 T cells and promoted their cytotoxic functions. Interestingly, over the chronic phase, IL-2Rβ-signals dramatically worsened CD8 T cell exhaustion. IL-2 and IL-15 sustained the expression of several inhibitory receptors and fostered the development of the highly exhausted PD-1hi progeny population. Finally, IL-2Rβ-signals precluded central memory CD8 T cell differentiation capable of homeostatic proliferation and robust secondary expansion. Altogether, these data demonstrated for the first time an important deleterious effect of IL-2 and IL-15 on the CD8 T cell response to a chronic viral infection. Reconsidering their role in this context may provide new insights for therapeutic regimens against chronic viruses.