HnRNPK restrains memory precursor and plasma cell differentiation to control germinal center B-cell output.

Germinal center (GC) B cells are critical for the production of long-lived plasma cells and high-affinity antibodies. Upon exiting the GC reaction, B cells differentiate into either memory B (MB) cells or plasma cells depending on affinity signals and transcription factor profiles. However, the underlying transcriptional and metabolic mechanisms regulating this fate decision remain poorly understood. Here, we generated mice with B and GC B-cell-specific knockout of heterogeneous nuclear ribonucleoprotein K (hnRNPK). We found that hnRNPK deletion partially impaired B-cell development and, more strikingly, markedly attenuated the GC B-cell response. The reduction in GC B-cell numbers was attributed to excessive differentiation of precursor MB cells and plasma cells during the GC reaction. Mechanistically, hnRNPK directly suppressed the expression of the key MB cell-associated transcription factors Hhex and Zfp318. Moreover, we observed that compared with CD25-negative GC B cells, CD25-positive GC B cells displayed elevated glycolytic gene expression and significantly increased glucose uptake. HnRNPK deficiency further upregulated glycolytic activity, promoted CD25 expression, and consequently enhanced plasma cell differentiation. Blocking IL‑2/CD25 signaling mitigated the excessive plasmablast differentiation induced by hnRNPK loss and rescued the GC defects in hnRNPK‑deficient mice. Together, these findings demonstrate that hnRNPK controls GC B-cell output by transcriptionally repressing the expression of the MB cell-differentiation factors Hhex and Zfp318 and by modulating the glycolysis‑CD25 regulatory axis.