Exogenous estrogen enhances T cell activation in male primates.

Estrogen influences T cell development and enhances infection resistance in females, but its immunological effects during gender-affirming hormone therapy (GAHT) remain poorly understood. Here, we characterize immune adaptations in male rhesus macaques (RMs) treated with 17β-estradiol (E2) or placebo over 7 months. E2 therapy suppressed endogenous testosterone production, induced female physical traits, and altered blood cell counts and chemistry profiles. Additionally, E2 treatment attenuated innate immune responses while increasing T cell activation. Following mRNA vaccination, E2-treated RMs exhibited significantly higher frequencies of CCR5 CD4 T cells, the primary targets for HIV-1 replication, compared to placebo-treated RMs. Overall, our findings reveal the immunological consequences of estrogen in male primates, emphasizing the need to investigate how supraphysiological E2 levels may affect HIV susceptibility and pathogenesis. This work highlights the potential of RMs as a model for studying immune interventions in the context of GAHT.