Cell-autonomous co-stimulatory function of membrane-bound CD100 promotes activation and differentiation of...

CD100/SEMA4D functions as a critical co-stimulatory molecule in T cell responses, existing in both membrane-bound (mCD100) and soluble (sCD100) forms. Previous studies have shown that CD100 enhances CD8⁺ T cell responses indirectly by promoting the maturation and activation of antigen-presenting cells, thereby facilitating viral clearance. However, whether mCD100, highly expressed on resting T cells, can also directly regulate CD8⁺ T cell function upon ligand engagement remains unclear.

We examined the impact of CD100 deficiency on the functional phenotype and differentiation of HBcAg-specific CD8⁺ T cells using separate and co-culture systems in vitro. Furthermore, through adoptive transfer of CD100 knockout HBV Cor93 TCR-transgenic (CD100KO C93-TCRtg) CD8⁺ T cells, we investigated the early impact of mCD100 deficiency on the development of HBcAg-specific CD8⁺ T cell responses during HBV infection.

The absence of mCD100 expression significantly decrease HBcAg-specific CD8⁺ T-cell proliferation, activation, effector cytokine production, and expression of Granzyme B and Eomes upon antigen stimulation in vitro. In the acute self-resolving models, the early proliferation of transferred CD100KO C93-TCRtg CD8⁺ T cells were impaired compared to their WT counterparts following HBV challenge. Transcriptomic data revealed that significant downregulation of gene sets associated with the PI3K-Akt, mTOR, NF-κB, and JAK-STAT signaling pathways in CD100KO CD8⁺ T cells.

Membrane CD100 expressed on resting HBcAg-specific CD8⁺ T cells may function as a co-stimulatory molecule by providing a direct stimulatory signal for the early proliferation and effector differentiation of T cells. The observed effects of mCD100 are associated with the PI3K-Akt-mTOR, JAK-STAT and NF-κB signaling pathways.