Decoding the impact of individual gamma-chain cytokines on exhausted CD8 T-cell biology 4280

Abstract Description CD8 T-cell exhaustion poses a significant challenge to cancer immunotherapies. Reversing this epigenetically stable state has proven difficult. Recent work, including ours, has demonstrated that the gamma-chain (γc) cytokine IL-2 can partially reprogram exhausted CD8 T-cells (Tex) toward more functional states, emphasizing the potential of γc-family of cytokines (IL-2/15, -4, -7, -9, -21) to reshape the Tex epigenome. However, the distinct effects of individual γc-cytokines on Tex biology remain unclear, precluding optimal clinical applications. Here, we used innovative orthogonal receptor-ligand pairs to deliver specific γc-signals in Tex cells and systematically compare their unique and overlapping impacts. Using the lymphocytic choriomeningitis virus (LCMV) model, a gold standard for studying T-cell exhaustion, we identified shared and cytokine-specific effects on Tex cell proliferation, effector functions, and differentiation. Multiomic single-cell sequencing revealed unique transcriptional and epigenetic remodeling by each γc-cytokine. These changes include disruption of exhaustion-related modules and reactivation of effector-associated enhancers. Specific epigenetic reprogramming by individual γc-cytokines highlights unexpected complementarities that could inform combinatorial therapeutic strategies. Our findings enhance understanding of γc-cytokine modulation in Tex cells and provide a framework for optimal integration of these cytokines into cancer immunotherapy. Funding Sources This work was supported by the National institute for Health (NIH) and the Parker Institute for Cancer Immunotherapy (E.J.W). JC.B is supported by the Swiss National Science Foundation (SNSF TMSGI3_218028), a Parker Institute for Cancer Immunotherapy bridge award and the Department of Biomedicine of the University of Basel (Switzerland). Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)