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Testosterone significantly alters immune responses in transgender men by dampening type-I interferon and boosting tumor necrosis factor pathways. These findings reveal dynamic immune regulation by sex hormones and impact understanding of sex differences in immunity.

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Area of Science:

  • Immunology
  • Endocrinology
  • Genetics

Background:

  • Infectious, inflammatory, and autoimmune diseases manifest differently between sexes.
  • Females exhibit stronger vaccine responses and higher rates of adverse reactions, alongside increased risk for long COVID.
  • Immunological sex distinctions arise from genetic, hormonal, and behavioral factors, with their interplay not fully elucidated.

Purpose of the Study:

  • To investigate the immunological consequences of gender-affirming testosterone therapy in transgender men.
  • To understand how testosterone modulates immune cell function and cytokine production.
  • To explore the implications for sex-divergent immune responses.

Main Methods:

  • Longitudinal systems-level analyses were conducted on 23 transgender men undergoing testosterone therapy.
  • Flow cytometry and cytokine assays were used to assess immune cell function and cytokine profiles.
  • Public datasets were analyzed to corroborate findings in cisgender populations.

Main Results:

  • Testosterone was found to modulate the interplay between type-I interferon and tumor necrosis factor (TNF).
  • Functional attenuation of type-I interferon responses was observed in plasmacytoid dendritic cells and monocytes.
  • Testosterone potentiated monocyte production of TNF, interleukin-6, and interleukin-15, activating NF-κB pathways and enhancing interferon-γ responses in natural killer cells.

Conclusions:

  • Testosterone dynamically regulates human immune responses, impacting type-I interferon and TNF signaling pathways.
  • Findings in transgender men provide insights into sex hormone influence on immunity, relevant to individuals on hormone therapy and cisgender populations.
  • This study highlights the critical role of sex hormones in shaping immune cell function and inflammatory responses.