Sex bias in MHC I-associated shaping of the adaptive immune system

Schneider-Hohendorf T, Görlich D, Savola P, Kelkka T, Mustjoki S, Gross CC, Owens GC, Klotz L, Dornmair K, Wiendl H, Schwab N

Abstract

Our analysis shows that sex can be associated with the degree to which HLA molecules propagate selection and expansion of T cells as characterized by their T cell receptor variable beta chain (TCRBV). Furthermore, CD8 T cells, especially in men with autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, are capable of expanding in unison with other CD8 T cells, even without expressing TCRBVs with biochemical similarity in pivotal HLA-binding regions. Our findings add to the understanding of sex bias in diseases with immune system involvement: autoimmunity, infection, and cancer. These results also reveal pathology-associated TCRBVs of interest for future studies and support the argument for sex-separated analysis of HLA disease associations in general.HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman’s rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.