Immune system adaptation during gender-affirming testosterone treatment.

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.