Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study

BackgroundSexual dimorphisms, which vary depending on age group and pubertal status, have been described across both the innate adaptive immune system. We explored influence of sex hormones phenotype in context adolescent health autoimmunity.MethodsIn this cross-sectional study, healthy, post-pubertal cisgender individuals (aged 16–25 years); pre-pubertal 6–11 transgender 18–19 years) undergoing gender-affirming treatment (testosterone assigned female at birth oestradiol male birth); 14–25 with juvenile-onset systemic lupus erythematosus (SLE) age-matched to without SLE were eligible for inclusion. Frequencies 28 immune-cell subsets (including different T cell, B monocyte subsets) from each participant measured peripheral blood mononuclear cells by flow cytometry analysed balanced random forest machine learning. RNA-sequencing was used compare gender differences regulatory (Treg) cell between participants SLE, cis-gender disease, matched hormone treatment. Differentially expressed genes cluster pathway analysis. Suppression assays assessed anti-inflammatory function Treg vitro.FindingsBetween Sept 5, 2012, Nov 6, 2019, collected 39 (17 [44%] men, mean 18·76 years [SD 2·66]; 22 [56%] women, 18·59 [2·81]), 14 children (seven [50%] boys, 8·90 [1·66]; seven girls, 8·40 [1·58]), ten people (five 18·20 [0·47]; five 18·70 [0·55]), 35 (12 [34%] 18·58 [2·35]; 23 [66%] 19·48 [3·08]). Statistically significantly elevated frequencies one top features differentiating young men similarly aged women (p=0·0097). had a statistically increased suppressive capacity vitro compared those distinct transcriptomic signature enriched PI3K–AKT signalling pathway. Gender-affirming induced multiple significant changes Treg-cell transcriptome, many functional pathways that overlapped altered highlighting hormonal gender. Finally, frequency absent reversed patients but transcriptional signatures more pronounced suggesting could be dysregulated autoimmunity.InterpretationSex-chromosomes might drive function. Young profile, explain inflammatory disease susceptibilities, inform sex-tailored therapeutic strategies.FundingVersus Arthritis, UK National Institute Health Research University College London Hospital Biomedical Centre, Lupus UK, The Rosetrees Trust.