T cells from newly diagnosed multiple sclerosis patients have enhanced responsiveness to <scp>CD46</scp> activation

Abstract Objective To evaluate the responsiveness of T cells from newly diagnosed multiple sclerosis (MS) patients to CD46 co‐stimulation, a membrane co‐factor protein potentially involved in MS pathogenesis. Methods T cells from MS patients and non‐diseased symptomatic controls (SC) were activated in vitro with or without αCD46 antibody co‐stimulation. Cytokine responses were measured to assess T‐cell responsiveness. The fold difference between αCD3/CD46 and αCD3/isotype responses was calculated to determine the enhancement of CD46 activation in MS compared with SC. Additionally, the CD46 receptor phenotype, including the expression of the CD46 CYT‐1 and CYT‐2 isoforms, was analyzed. Results In the absence of αCD46 co‐stimulation, MS T cells showed weaker cytokine responses compared to SC. However, CD46 engagement neutralized this deficit, resulting in a higher fold difference in MS αCD3/CD46 responses compared to SC. MS T cells also showed a trend toward a biased CD46 receptor phenotype, with a preference for the CD46 CYT‐2 isoform. Conclusions CD46 activation enhances T‐cell responses in newly diagnosed MS patients. A bias toward the CD46 CYT‐2 isoform is observed, aligning with the previous findings that the absence of CYT‐2 downregulation in MS might contribute to a pro‐inflammatory environment.