N-glycosylation is essential for aberrant Tfh cells differentiation in systemic lupus erythematosus.

Aberrant differentiation of T follicular helper (Tfh) cells contributes to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). However, whether Tfh cell differentiation is regulated by glycosylation remains unclear. In this study, we found that inhibition of N-glycosylation completely blocked Tfh cell differentiation. Critical molecules that define Tfh cell function, including CXCR5, PD-1, and IL-21, were found to contain multiple N-glycosylation motifs (conserved Asn-X-Ser/Thr sequences) based on amino acid sequence analysis. Notably, multiple genes encoding enzymes involved in different stages of N-glycosylation were highly expressed in peripheral CD4 T cells from patients with SLE, particularly in those with active disease. Together, these findings implicate the role of N-glycosylation in the regulation of aberrant Tfh cell differentiation. Further elucidation of the mechanisms underlying N-glycosylation dysregulation in SLE will provide a critical foundation for understanding disease pathogenesis and facilitating the identification of novel therapeutic targets.