IL-2 Signals Program the Fate of Exhausted CD8 T cells

Abstract

Abstract The high affinity IL-2 receptor (IL-2Ra, CD25) is a key activation marker, which is transiently and heterogeneously expressed during the priming . While IL-2 signals are deemed critical for expansion of antigen-specific CD8 T cells, the role of IL-2 in programing the fate of exhausted CD8 T cells in vivo is poorly understood. Exhausted CD8 T cells are broadly divided into 2 subsets: one with brightest levels of inhibitory receptors such as PD-1, and lower mitochondrial spare respiratory capacity (SRC) – these cells are terminally exhausted and are largely unresponsive to PD-1 checkpoint blockade immunotherapy. The other subset has intermediate levels of inhibitory receptors and retains higher mitochondrial SRC – these are the clinically relevant cells that are highly responsive to PD-1 blockade. Based on the ability of IL-2 signals to drive glycolytic burnout in T cells, we hypothesized that the stochastic heterogeneity in in vivo assimilation of IL-2 signals during priming drives distinct CD8 T cell fates late during exhaustion. We sorted in vivo primed CD8 T cells based on their heterogeneity in CD25 expression, and adoptively transferred them into infection-matched chronically infected recipients. We observed that the exhausted CD8 T cells generated from CD25Hi donor cells phenotypically and functionally resembled terminally exhausted cells. Furthermore, knocking down the expression of CD25 or Special AT-rich sequence binding protein 1 (SATB1), which is known to regulate CD25 expression, resulted in better survival and function of exhausted CD8 T cells. Our data underscores the critical role of IL-2 signals in the exhaustion of CD8 T cells and has clinical significance in current combination checkpoint blockade immunotherapies.