The study by Chowdhury and colleagues provides compelling evidence that AR activity plays a critical role in regulating Th17 cell metabolism and function in allergic airway inflammation (10). Their findings demonstrate that androgen signaling limits glutaminolysis in Th17 cells in males, resulting in reduced airway inflammation. While these insights are crucial, they also highlight the need to explore the broader implications of hormone-mediated metabolic regulation in immune cells across different contexts. The complexity of Th17 cell biology and its relationship with sex hormones extends beyond the lung inflammation model used in this study, as evidenced by the varied sex-based prevalence of Th17-associated autoimmune diseases. The variability in sex bias may be partly explained by the diverse roles and metabolic status of Th17 cells in different tissues. For instance, prior research has identified metabolically distinct pathogenic and protective Th17 cells in the intestines, demonstrating that metabolism may differ based on Th17 tissue context and function (14). Interestingly, the incidence of Crohn’s disease, thought to be driven in part by Th17 cell–mediated inflammation, increases in women following puberty, suggesting a potential role for estrogens in modulating disease risk (15). This observation, coupled with Chowdhury and authors’ (10) data showing that loss of estrogen receptor on T cells reduces disease severity in females, underscores the complex and sometimes opposing roles that different sex hormones can play in immune regulation. These findings highlight the need for a nuanced understanding of how androgens, estrogens, and other sex-specific hormones interact to shape Th17 cell function and immune responses across various tissues and disease contexts.

While the study by Chowdhury et al. (10) provides crucial insights into the role of androgen signaling in Th17 cell function, it also raises intriguing questions about the broader landscape of Th17 cell metabolism. Previous research has established that cell metabolism plays a critical role in Th17 cell differentiation and function (14, 16), with the balance of glycolysis and oxidative phosphorylation being particularly important for their inflammatory activity (17–19). This study breaks new ground by highlighting the regulation of glutamine metabolism by sex hormones in Th17 cells (10). However, mechanistic questions remain about how precisely glutamine metabolism enhances Th17 cell function. Glutamine serves multiple functions in T cells, including fueling the TCA cycle, contributing to glutathione synthesis, and generating α-ketoglutarate, which acts as a signaling molecule influencing metabolic adaptations and gene expression. Intriguingly, the authors demonstrate that the level of reactive oxygen species (ROS) in male Th17 cells is sensitive to AR activity, and loss of AR signaling in male Th17 cells increases glutamine flux to glutathione. These observations support a potential link between AR signaling, glutamine metabolism, oxidative stress, and Th17 cell development and function, as proposed by other recent studies (20, 21). However, more work is needed to fully elucidate this mechanism and its implications for Th17-mediated immune responses and related diseases.

In summary, the work of Chowdhury et al. (10) illuminates the complex interplay between androgen signaling, Th17 cell metabolism, and immune function, while also opening avenues for future research. Key questions remain: How do hormonal fluctuations across different physiological states affect Th17 metabolism and immune responses? Can we leverage our understanding of sex-specific metabolic pathways to design more effective therapeutic interventions? Future studies should explore these sex differences in Th17 metabolism across various organs and disease states, potentially leading to targeted therapies that account for the intricate relationship between sex hormones, cellular metabolism, and immune function. Such research could markedly advance our approach to treating mediated autoimmune and inflammatory diseases.