KDM5C-regulated anabolic metabolism is required for T cell expansion

Introduction/Rationale: Clonal expansion of T cells is a critical component of the adaptive immune response necessary for combating a diverse range of pathogens. Clonal expansion of T cells is a unique physiological process that enables the immune system to generate a large number and is highly controlled by metabolic reprogramming. This metabolic programming is orchestrated through signaling pathways such as PI3K, AKT/PKB and mTOR and key downstream including MYC, SREBPs and HIF1a that program anabolic metabolism. We have found that the KDM5C (JARID1C/SMCX) is a histone demethylase that removes methyl groups from lysine 4 on histone 3 (H3K4) is critical for CD8 T cell expansion during infection. We examined whether KDM5C links epigenetic modulation to the anabolic requirements of clonal expansion during immune responses.

Methods: We used adoptive T cell Tg models to establish that KDM5C is intrinsically required for T cell expansion. RNA-seq revealed extensive regulation of metabolic genes by KDM5C. We used metabolomics coupled with stable isotope tracing (SIL) to assess anabolism and immunoblot to validate the gene expression findings .CUT&TAG was used to define KDM5C genome occupancy.

Results: We found that KDM5C expression is rapidly upregulated following T cell activation and is necessary for the transcriptional activation of genes involved in anabolic metabolism. Loss of KDM5C results in reduced levels of metabolites central to nucleotide biosynthesis, the tricarboxylic acid (TCA) cycle, and fatty acid synthesis. Correspondingly, we found that KDM5C promotes the expression of key transcription factors that drive anabolic programming via a histone-demethylase-independent mechanism.

Conclusion: This newly identified role positions KDM5C as a critical integrator of transcriptional and metabolic networks that sustain T cell clonal expansion during infection.