Single-cell gain of function screens reveal synthetic regulators of T cell stemness in vivo

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Presentation Time: 09:15 AM - 09:30 AM
Abstract ID: 4344 - B

Presenting Author:
Genevieve N Mullins , Post-doctoral fellow at Univ. of North Carolina, Chapel Hill

Abstract:

In the context of chronic viral infections and cancer, CD8 T cells differentiate into a dysfunctional lineage referred to as exhausted cells. Here, we applied single-cell gain-of-function genetic screens to uncover transcription factors that modulate T cell exhaustion when artificially overexpressed in vivo. We uncovered numerous synthetic alterations that blunt exhaustion, modulate T cell differentiation trajectories, enhance accumulation, and confer new functional phenotypes during chronic infection and cancer. We assign new roles to canonical regulators of T cell differentiation such as Blimp1 and Runx3, and we also uncovered unexpected roles for transcription factors that are conventionally silenced in T cells. Notably, we found that sustained expression of cMyc led to dramatic reprogramming of T cell exhaustion in infection and tumors, and dramatically enhanced the accumulation of effector-like cells. Although CD8 T cells rapidly suppress Myc expression during infection and cancer, we show that artificially sustained cMyc activity transcriptionally and epigenetically reprograms CD8 T cells for improved functional potential. Last, the reprogramming power of sustained Myc function is at least partially dependent on suppression of Blimp1 activity in vivo. Together, these studies highlight the exciting potential of harnessing gain-of-function alterations in CD8 T cells for enhancing their function during settings of persistent antigen.