EFHD2 regulates T cell receptor signaling and modulates T helper cell activation in early sepsis

EFHD2 (EF-hand domain family, member D2) has been identified as a calcium-binding protein with immunomodulatory effects. In this study, we characterized the phenotype of Efhd2-deficient mice in sepsis and examined the biological functions of EFHD2 in peripheral T cell activation and T helper (Th) cell differentiation. Increased levels of EFHD2 expression accompanied peripheral CD4⁺ T cell activation in the early stages of sepsis. Transcriptomic analysis indicated that immune response activation was impaired in Efhd2-deficient CD4⁺ T cells. Further, Efhd2-deficient CD4⁺ T cells isolated from the spleen of septic mice showed impaired T cell receptor (TCR)-induced Th differentiation, especially Th1 and Th17 differentiation. In vitro data also showed that Efhd2-deficient CD4⁺ T cells exhibit impaired Th1 and Th17 differentiation. In the CD4⁺ T cells and macrophages co-culture model for antigen presentation, the deficiency of Efhd2 in CD4⁺ T cells resulted in impaired formation of immunological synapses. In addition, Efhd2-deficient CD4⁺ T cells exhibited reduced levels of phospho-LCK and phospho-ZAP70, and downstream transcription factors including Nfat, Nfκb and Nur77 following TCR engagement. In summary, EFHD2 may promote TCR-mediated T cell activation subsequent Th1 and Th17 differentiation in the early stages of sepsis by regulating the intensity of TCR complex formation.