Testosterone affects female CD4+ T cells in healthy individuals and autoimmune liver diseases
Lara Henze, Nico Will, Dakyung Lee, Victor H. Haas, Christian Casar, Jasper Meyer, Stephanie Stein, Franziska Mangler, Silja Steinmann, T Poch, Jenny Krause, Johannes Fuß, Johanna Schröder, Alexandra Kulle, Paul‐Martin Holterhus, Stefan Bonn, Marcus Altfeld, Samuel Huber, Ansgar W. Lohse, Dorothee Schwinge, Christoph Schramm
Abstract
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.