PRISM · Beyond the binary: ProgRammIng of Sexual immune identity from thyMus to tissues

Sexual dimorphism is a fundamental aspect of biology. Nearly all diseases show sex differences, yet sex is usually treated as a variable to stratify by, rather than as a key question to explore. In immunology, females mount stronger T cell responses and show higher rates of autoimmunity, while males are more vulnerable to infections and weaker vaccine responders. These differences are often attributed to local hormonal effects, but whether they also reflect central developmental programming remains unknown. Hormonal manipulation, such as HRT or GAHT, are widely used in Europe but their effects on the immune system remain unknown. PRISM proposes that the thymus, an androgen-sensitive and sexually dimorphic organ, acts as a hub where androgens imprint long-lasting immune sexual features that shape peripheral T cell responses, particularly in barrier tissues such as the skin. Preliminary evidence supports this model: androgens are enriched in the thymus, human thymocytes express the androgen receptor, and transgender men undergoing testosterone therapy show reduced thymic output of naïve T cells.PRISM will address three questions: 1) How do androgens influence the physiology of sex-biased thymic function? 2) Which thymic programs translate androgenic signals into dimorphic T cell development? 3) What is the impact of androgenic treatments on central and peripheral immunity? To answer these, I will combine in vivo hormonal manipulation in mice, conditional genetics, infection models with antigen-specific T cells, and single-cell/spatial transcriptomics.If successful, PRISM will deliver the first mechanistic framework linking endocrine cues, thymic programs, and barrier immunity, and will define the plasticity of immune sexual dimorphism. At a broader level, PRISM aligns with the EU’s Roadmap for Women’s Rights and the 2026-30 Gender Equality Strategy, positioning Europe at the forefront of gender-informed immunology, with direct biomedical and societal relevance.