Immune system adaptation during gender-affirming testosterone treatment

• 成果类型: Article
• 署名作者: Lakshmikanth, Tadepally; Consiglio, Camila; Sardh, Fabian; Forlin, Rikard; Wang, Jun; Tan, Ziyang; Barcenilla, Hugo; Rodriguez, Lucie; Sugrue, Jamie; Noori, Peri; Ivanchenko, Margarita; Paez, Laura Pinero; Gonzalez, Laura; Mugabo, Constantin Habimana; Johnsson, Anette; Ryberg, Henrik; Hallgren, Asa; Pou, Christian; Chen, Yang; Mikes, Jaromir; James, Anna; Dahlqvist, Per; Wahlberg, Jeanette; Hagelin, Anders; Holmberg, Mats; Degerblad, Marie; Isaksson, Magnus; Duffy, Darragh; Kampe, Olle; Landegren, Nils; Brodin, Petter
• 署名单位: Karolinska Institutet; Lund University; Karolinska Institutet; Uppsala University; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Sahlgrenska University Hospital; University of Gothenburg; Umea University; Orebro University; Karolinska Institutet; Karolinska University Hospital; Karolinska Institutet; Karolinska Institutet; Uppsala University; Karolinska Institutet; Karolinska University Hospital; Imperial College London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3794
• DOI: 10.1038/s41586-024-07789-z
• 发表日期: 2024-09-05
• 页码: 155-164
• 关键词: plasmacytoid dendritic cells; necrosis-factor-alpha; ifn-alpha; t-cells; in-vivo; sex; responses; AGE; Visualization; infection

摘要

Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-gamma responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals. Examination of immunological changes in transgender individuals undergoing gender-affirming testosterone treatment reveals sex hormone-regulated pathways in humans and explains sex-divergent responses in cisgender individuals.