Resistance to T cell exhaustion

点击翻译按钮获取中文摘要

PROJECT SUMMARY The overarching goals of this proposal are to define how intrinsic IL-2 production and extrinsic IL-2 signals act in conjunction with helper CD4 T cell subsets to configure the exhausted CD8 T cell pool during chronic viral infections and ascertain how these factors contribute to the restoration of responses following checkpoint blockade therapies. This is significant for providing both fundamental insights into the regulation of exhausted T cell ontogeny as well as for devising strategies to structure this ensemble to improve infection control while avoiding immunopathology. The premise is founded in part on a series of exciting published and preliminary findings showing that the pace of viral control can be predicted by the number of IL-2 producing CD8 T cells present at the peak of the effector phase of the anti-viral response. Moreover, the initial formation of IL-2 producing CD8 T cells is accelerated during the earliest stages of chronic viral infections, but this population fails to amplify, suggesting that they may instead serve as progenitors for the development of transitional and terminally exhausted subsets. We also discovered that IL-2-producing effector CD8 T cells generated during acute infections have superior protective powers and are resistant to full terminal exhaustion following adoptive transfer and chronic viral challenge. Additionally, our preliminary findings demonstrate that the cell-autonomous synthesis of IL-2 attenuates the ability to receive STAT5 signals. Collectively, these findings are consistent with a model in which the initial manufacture of IL-2 enables exhausted precursor formation by restricting STAT5- mediated signals, which are known to drive terminal differentiation. Further, we anticipate that the subsequent extinguishment of IL-2 synthesis restores permissiveness to STAT5 signaling, which prompts the further developmental transition of these precursors into more exhausted sub-populations. Our studies are designed to pin-point how intrinsic cytokine production and extrinsic cytokine signals direct the formation and maintenance of exhausted subsets, and provide new insights into the mechanisms that shape the efficacy of the anti-viral T cell pool during chronic infections. We propose the following specific aims: 1. Define the contributions of IL-2-producing CD8 T cells to the formation of exhausted subsets. 2. Define the influence of functionally distinct CD4 helper subsets on the exhausted pool. 3. Determine the temporally distinct roles of IL-2 in structuring the exhausted pool. Our studies take advantage of innovative and technically robust approaches to deconvolute the roles of distinct cytokine producing subsets of anti-viral T cells during chronic infections. They are designed to impact the field by advancing our understanding of how intrinsic cytokine production and extrinsic cytokine and cellular signals integrate to configure the exhausted CD8 T cell pool and contribute to the control of chronic viral infections.