Testosterone affects female CD4+ T cells in healthy individuals and autoimmune liver diseases
Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are autoimmune liver diseases with strong female predominance. They are caused by T cell-mediated injury of hepatic parenchymal cells, but the mechanisms underlying this sex bias are unknown. Here, we investigated whether testosterone contributes to T cell activation in women with PBC. Compared with sex- and age-matched healthy controls (n = 23), cisgender (cis) women with PBC (n = 24) demonstrated decreased testosterone serum levels and proinflammatory CD4+ T cell profile in peripheral blood. Testosterone suppressed the expression of TNF and IFN-γ by human CD4+ T cells in vitro. In trans men receiving gender-affirming hormone therapy (GAHT) (n = 25), testosterone affected CD4+ T cell function by inhibiting Th1 and Th17 differentiation and by supporting the differentiation into regulatory Treg. Mechanistically, we provide evidence for a direct effect of testosterone on T cells using mice with T cell-specific deletion of the cytosolic androgen receptor. Supporting a role for testosterone in autoimmune liver disease, we observed an improved disease course and profound changes in T cell states in a trans man with AIH/primary sclerosing cholangitis (PSC) variant syndrome receiving GAHT. We here report a direct effect of testosterone on CD4+ T cells that may contribute to future personalized treatment strategies.
Authors
- Alexandra Kulle (ORCID: https://orcid.org/0000-0002-4411-6879)
- Stefan Bonn (ORCID: https://orcid.org/0000-0003-4366-5662)
- Christoph Schramm (ORCID: https://orcid.org/0000-0002-4264-1928)
- Stephanie Stein (ORCID: https://orcid.org/0000-0003-3827-8473)
- Jasper Meyer
- Marcus Altfeld (ORCID: https://orcid.org/0000-0001-5972-2997)
- Victor H. Haas
- Johannes Fuß (ORCID: https://orcid.org/0000-0003-0445-5021)
- Dorothee Schwinge (ORCID: https://orcid.org/0000-0002-0679-4476)
- T Poch (ORCID: https://orcid.org/0000-0001-8178-9522)
- Dakyung Lee
- Silja Steinmann (ORCID: https://orcid.org/0000-0001-9177-1414)
- Ansgar Wilhelm Lohse (ORCID: https://orcid.org/0000-0002-8823-3129)
- Lara Henze (ORCID: https://orcid.org/0000-0001-9585-7864)
- Jenny Krause (ORCID: https://orcid.org/0000-0002-8657-881X)
- Paul‐Martin Holterhus (ORCID: https://orcid.org/0000-0002-9308-3129)
- Christian Casar (ORCID: https://orcid.org/0000-0002-8624-1045)
- Johanna Schröder (ORCID: https://orcid.org/0000-0002-0751-4720)
- Samuel Huber (ORCID: https://orcid.org/0000-0001-9325-8227)
- Nico Will
- Franziska Mangler
Institutions
- Leibniz Institute of Virology (LIV) (DE)
- Universität Hamburg (DE)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Schleswig-Holstein (DE)
- Center for Translational Molecular Medicine (NL)
- Institute of Medical Biology (SG)
- University of Duisburg-Essen (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-04-21
- DOI
- https://doi.org/10.1172/jci.insight.184544
- Citations
- 8
- Primary Topic
- Liver Diseases and Immunity
- Type
- article
- Field-Weighted Citation Impact
- 10.58
Funders
- Deutsche Forschungsgemeinschaft