Fazazi, M. R. | bioRxiv Science

bioRxiv2026

The antagonism of sex chromosomes and sex hormones dictates outcomes in Th17 cell-mediated central nervous system autoimmunity.

Biological sex traits are shaped by the combined effects of both sex hormones and chromosomes. How these factors interact in sex-related autoimmune diseases, such as multiple sclerosis (MS), has been a subject of intense recent interest. Here, using the Four Core Genotype (FCG) mouse model, in which these two variables can be disentangled, we describe an antagonism between sex hormones and chromosomes that potently influences outcomes in T helper 17 (Th17)-driven progressive central nervous system (CNS) autoimmunity. Male gonadal hormones dampen disease severity, irrespective of sex chromosome complement, by promoting a Wnt/{beta}-catenin signaling program associated with a homeostatic, non-pathogenic Th17 phenotype. By contrast, XY chromosomal complement exacerbates Th17 pathogenicity in a recipient sex-dependent manner; we identify the X-linked molecule SUV39H1 as an inhibitor of inflammatory Th17 cell function. Unexpectedly, we found that hormonally and chromosomally female FCG Th17 cells induced far more severe disease than WT female counterparts despite being genetically identical, pointing to a parental imprinting effect in dictating Th17 cell pathogenicity. These latter investigations uncovered Runx2, a transcription factor previously linked to developmental programs, as a novel negative regulator of the pathogenicity of Th17 cells. Together, our findings establish biological sex as a multilayered regulator of Th17 pathogenicity, revealing distinct and sometimes opposing contributions of hormones, chromosomes, and parental inheritance.

immunology↗

bioRxiv2025

Myelin antigen-specific effector CD8+ T cells induce chronic CNS autoimmunity in a CD4+ T cell-dependent manner.

Both CD4+ and CD8+ T cells play critical roles in the immunopathogenesis of multiple sclerosis (MS). 1C6 T cell receptor transgenic (TcR-Tg) mice on the nonobese diabetic (NOD) background have a MOG[35-55]-specific, MHC class II-restricted, TcR that selects for both CD4+ and CD8+ T cells. Adoptive transfer of 1C6 CD4+ T helper 17 (Th17) cells can induce experimental autoimmune encephalomyelitis (EAE) with a progressive disease course. In the current study, we assessed the function and pathogenicity of 1C6 CD8+ T cells. We found that they proliferated and produced inflammatory cytokines in response to MOG[35-55] peptide under both T cytotoxic 1 (Tc1) and Tc17 differentiation conditions, albeit with reduced expansion relative to their Th1 or Th17 counterparts. Both 1C6 Tc1 and Tc17 cells were able to induce EAE upon adoptive transfer to NOD.Scid mice. Intriguingly, we noted in vivo expansion of CD4+ T cells in the spleen and CNS of NOD.Scid recipients as well as in lymphocyte-sufficient animals, despite 1C6 Tc cells being purified on CD8 expression prior to transfer. Furthermore, 1C6 Tc17 cells expressed ThPOK, a master differentiation factor for CD4+ T cells. Finally, anti-CD4+ T cell blockade abrogated CD8+ T cell infiltration of the CNS and disease induction in Tc17 recipient mice. Our data provide insight into the interplay of CD4+ and CD8+ T cells in CNS autoimmunity.

immunology↗