CD74-Pax5 Regulates B-cell Function via PI3K/AKT Signaling Pathway in Sepsis

Sepsis-induced B-cell dysfunction is a pivotal driver of adaptive immunosuppression, although the underlying molecular mechanisms remain incompletely elucidated. CD74, a multifunctional immunoregulatory protein, is known to mediate tumor immune evasion and immunosuppression during infection via modulation of inflammatory pathways; however, its specific role in B-cell dysfunction during sepsis has not been defined. Through integrated clinical and experimental analyses, we observed significant downregulation of CD74 in the peripheral blood of septic patients (based on GSE datasets), which correlated with adverse clinical outcomes. Validation in a cecal ligation and puncture-induced sepsis model in C57BL/6J mice demonstrated that CD74 deficiency markedly increased mortality, elevated pro‑inflammatory cytokine levels (tumor necrosis factor‑α, interleukin [IL]‑6, IL‑1β, monocyte chemoattractant protein-1; measured by enzyme-linked immunosorbent assay), and impaired bacterial clearance. Mechanistically, CD74 is a member of the regulated intramembrane proteolysis protein family. Following intramembrane cleavage, its intracellular domain (CD74‑ICD) is released and translocates to the nucleus, where it interacts with the key transcription factor Pax5 (as confirmed by co‑immunoprecipitation and immunofluorescence). This interaction leads to activation of the PI3K‑AKT signalling pathway, thereby preserving B-cell functional competence. Single‑cell transcriptomic analysis further supported the functional relevance of the CD74‑Pax5 axis in septic B cells. In summary, this study identifies CD74 as a critical regulator of sepsis-associated B-cell immunosuppression and highlights its therapeutic potential for immune reconstitution in sepsis.