Early heterogeneity of IL2R□ expression influences the programming of exhausted CD8T cells during chronic infection

Abstract IL-2 signaling at the time of CD8 T cell activation is a critical factor dictating effector and memory CD8 T cell differentiation. However, how IL-2 signaling impacts exhausted CD8 T cell fate outcomes remains poorly defined. Here, we address the role of IL-2 signaling in regulating the differentiation of the stem-like and terminally exhausted CD8 T cells. Prolonged expression of the high affinity IL-2 receptor (IL-2Ra, CD25), and resultant increase in IL-2 signaling drives terminal differentiation of effector cells during acute infection. We hypothesized that curtailing this signal would prevent terminal differentiation and promote the formation of less exhausted stem-cell like TCF-1+CD8T cells in chronic antigenic setting. Our studies show that blocking IL-2 signals at the early phase of chronic infection significantly increased the proportions of TCF-1+CD8T cells. Similarly, knocking down Il2ra augmented the development of TCF-1+CD8T cells. The therapeutic success of PD-1/PD-L1 checkpoint blockade immunotherapy (CBI) relies primarily on stem-cell like cells for vigorous expansion and effector responses. Thus, we next investigated how FACS-purified CD25Hi and CD25Lo cells adoptively transferred into infection-matched chronically infected recipients respond to PD-1 CBI. In contrast to CD25Hi cells, CD25Lo cells underwent vigorous proliferation after PD-1 CBI and produced high amount of effector molecules (GzmB, TNF-α and IFN-γ). Collectively, these data highlight the role of IL-2 signaling in the regulation of CD8 T cell exhaustion, which may be therapeutically exploited to optimize treatments of chronic infections and cancers with immune checkpoint inhibitors. Supported by NIH R21AI154363 NIH R01AI32819