Thymic selection of the T cell receptor repertoire is biased toward autoimmunity in females

Women represent about 80% of patients with autoimmune diseases. This may partly result from sex-based differences in T cell receptor (TCR) selection during thymocyte development, potentially influenced by hormones and the lower expression of the Autoimmune Regulator (AIRE) transcription factor in females.

To investigate this, we analyzed sex-specific differences in TCR generation and selection. We examined TCR repertoires in double-positive thymocytes and single-positive thymic cells, including CD8⁺ and CD4⁺ effector T cells and regulatory T cells (Tregs), derived from male and female organ donors. Minimal sex-based differences were observed in V and J gene usage, and there were no notable differences in TCR repertoire diversity, complementarity-determining region 3 (CDR3) length, amino acid composition, or network structure. No TCR sequences were exclusive to either sex.

However, female effector T cells exhibited a significantly higher prevalence of TCRs specific to self-antigens implicated in autoimmunity compared to males, while female Tregs showed a reduced frequency of such TCRs. These differences were not observed for TCRs targeting self-antigens unrelated to autoimmunity or antigens associated with cancer or viruses.

Our findings highlight a sex-specific imbalance in thymic selection of TCRs with autoimmunity-associated specificities, providing mechanistic insight into the increased susceptibility of women to autoimmune diseases.