Loss of LDH-A accelerates CD8+ T memory cell differentiation 2252161

Abstract

Abstract Introduction Lactate Dehydrogenase A (LDH-A) catalyzes the final step of glycolysis and is critical for hematopoietic stem cell survival and pluripotency. While activated T cells depend on glycolysis for effector functions, the role of LDH-A in CD8+ T cell differentiation remains unclear. Methods We investigated this using conditional LDH-A deletion in OT-I TCR transgenic mouse T cells. Results Following Listeria monocytogenes—OVA infection, OTI/LDH-A-/- CD8+ T cells showed reduced expansion at day 8 but higher frequency of central memory precursors. Transcriptomic analysis revealed enrichment of Bcl6 and Tcf7, markers of TMEM identity. Upon rechallenge at day 60, OTI/LDH-A-/- TMEM cells mediated superior pathogen clearance capacity compared to control OTI TMEM, leading to significantly reduced CFUs. To test anti-tumor immunity, we transferred OTI or OTI/LDH-A-/- cells into syngeneic hosts bearing B16-F10-OVA melanoma. Surprisingly, hosts receiving OTI/LDH-A-/- cells developed larger tumors with fewer CD8+ T cell infiltrates, which exhibited features of exhaustion, including elevated TIM-3 and reduced SLAMF6 and CD62L expression. Conclusion Our findings reveal that LDH-A deficiency skews CD8+ T cells toward a memory-like program, enhancing recall responses to infection but impairing effector differentiation and tumor control. Thus, LDH-A emerges as a key regulator balancing memory and effector differentiation and function across distinct immune contexts. Funding Source R01CA238263, R01CA257672 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)