Early Growth Response 2 (EGR2) Regulates Late B Cell Differentiation and Double-Negative T Cells in Lupus-Prone MRL/lpr Mice 2307921

Introduction Early Growth Response 2 (EGR2) is a zinc-finger transcription factor known to regulate T cell activation and tolerance; however, its role in B cell differentiation in lupus remains unclear. To define its function, we generated conditional Egr2 deletion in lupus-prone MRL/lpr mice and investigated its impact on B cell differentiation and pathogenic double-negative T (DNT) cells. Methods We generated CD2-Cre Egr2-deletion MRL/lpr mice and analyzed their immune phenotype. Using flow cytometry, we profiled splenic B cell subsets, germinal center (GC) B cells, plasmablasts, and double-negative T (DNT) cells. Serum immunoglobulins and autoantibodies were measured by ELISA. To assess immune activation and pathology, we evaluated IL-17 induction in stimulated splenocytes and performed histopathological scoring of major organs. Results Egr2 deletion caused a significant reduction in marginal zone B cells while sparing follicular B cells. GC B cells were markedly increased, but plasmablasts were significantly reduced, indicating impaired late B cell differentiation. DNT cells were dramatically decreased, accompanied by reduced IL-17 induction. Total IgG, IgM, anti-cardiolipin, and anti-Sm levels were unchanged. Histopathology showed a trend (but statistically not significant) towards reduced kidney inflammation but increased lymphoid hyperplasia and lung involvement. Conclusion EGR2 is a key regulator of B cell maturation and DNT cell expansion in lupus. Its deletion disrupts late B cell differentiation and alters tissue pathology, revealing a central transcriptional control mechanism in lupus immunopathogenesis.