Histone methyltransferase NSD2 shapes CD8+ T cell fates through the H3K36me2-Zbtb20 axis.

CD8+ T cells, as the most important cytolytic cells in adaptive immunity, can differentiate into distinct subpopulations with specific functions and fates. During this process, CD8+ T cells exhibit substantial plasticity in their differentiation trajectory. Notably, epigenetic regulation has emerged as a pivotal mechanism to govern T cell fate decisions. In this study, we demonstrate that the histone methyltransferase NSD2 critically regulates CD8+ T cell differentiation during acute viral infection. While NSD2 deficiency enhances the early expansion of activated CD8+ T cells, it severely compromises their survival fitness during the contraction phase, leading to a disproportionate collapse of the antigen-specific pool and limiting the establishment of robust long-lived memory. Mechanistically, this defect is driven by the disruption of the H3K36me2-Zbtb20 regulatory axis. Furthermore, we show that in the absence of NSD2, CD8+ T cells in tumor exhibit an increased proportion but dysfunctional resident memory T cell phenotype. Collectively, our findings highlight a critical role for NSD2 in providing more mechanistic insights into how epigenetic mechanisms fine-tune T cell differentiation.