Differential Effects of IL4I1 Protein on Lymphocytes From Healthy and Multiple Sclerosis Patients

• DOI: 10.1002/prp2.70062
• Publication Date: 2025-03-19T03:03:46Z
• Authors: Stephanie E. Davis; Jingwen Hu; Sonia E. Nanescu; Mahesh N. Kumar; Maryna Baydyuk; Helena C. Oft; Faria S. Amjad; Anton Wellstein; Jeffrey K. Huang

ABSTRACTMultiple sclerosis (MS) is a chronic inflammatory disease characterized by immune‐mediated demyelination of the central nervous system, resulting in extensive neurological deficit and remyelination impairment. We have previously found that interleukin‐four induced one (IL4I1) protein modulates CNS inflammation and enhances remyelination in mouse models of experimental demyelination. However, it remained unclear if IL4I1 regulates lymphocyte activity in MS. To assess the therapeutic potential of IL4I1 in MS, we investigated the impact of IL4I1 treatment on human lymphocytes from peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals and MS patients. We found that IL4I1 increased the relative densities of Th2 and regulatory T‐cells, while reducing Th17 cell density in healthy control (HC) samples. Furthermore, IL4I1‐treated lymphocytes promoted CNS remyelination when grafted into demyelinated spinal cord lesions in mice. We found that baseline endogenous IL4I1 expression was reduced in people with MS. However, unlike HCs, IL4I1 treatment had no significant effect on IL17 or TOB1 expression in lymphocytes derived from MS patients. These results suggest that IL4I1 skews CD4+ T‐cells to a regulatory state in healthy human lymphocytes, which may be essential for promoting remyelination. However, IL4I1 appears unable to exert its influence on lymphocytes in MS, indicating that impaired IL4I1‐mediated activity may underlie MS pathology.