Understanding sex-related differences in immune responses

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Science Translational Medicine  29 Jul 2020:
Vol. 12, Issue 554, eabd3631
DOI: 10.1126/scitranslmed.abd3631


Sex hormone–related changes in neutrophil responsiveness to interferons may underlie differences in immune responses.

Differences in immune responses between females and males are a well-recognized but undefined phenomenon. Females have more effective immune responses against immunization and infection, including against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but are disproportionately affected by autoimmune diseases. Identifying mechanisms underlying sex-related differences is essential for developing approaches to effectively modulate immune responses. In this study, Gupta et al. identified neutrophil responsiveness to a key immune signaling molecule, type I interferon (IFN-I), as a novel sex-related difference in immune system function.

Neutrophils are the most abundant type of leukocyte in the body, responsible for the earliest immune response against infection. The authors found that neutrophils from female subjects had increased expression of a key set of interferon-stimulated genes (ISGs) responsible for regulating responsiveness to stimulation and subsequent effector function. Single-cell gene expression analysis indicated that ISG up-regulation was specific to neutrophils and related to neutrophil maturation status. This was not attributable to differences in circulating IFN-I or expression of IFN-I receptors on the cell surface. Instead, the authors found that even in the absence of activation, female neutrophils were poised for increased responsiveness to IFN-I stimulation, with key transcription factors preferentially localized to the nucleus and available for IFN-I–driven activity. In contrast, male neutrophils demonstrated predominantly cytosolic localization of these factors, indicating a less IFN-I–responsive state. The authors found that male neutrophils had increased mitochondrial mass and basal metabolism, consistent with a previously described immature phenotype. Notably, treatment of male neutrophils with the female sex hormone estradiol reduced basal metabolism and moved the neutrophils toward a more “female” phenotype.

The influence of estradiol on the metabolic phenotype of neutrophils represents a novel definable effect of sex hormones on immune cell function. However, the influence of sex hormones on ISG expression and IFN-I responsiveness of neutrophils remains to be demonstrated. Similarly, the functional consequences of these changes on immune responses with known sex-related differences, such as autoimmunity or response to infection, need to be examined. Nonetheless, these findings represent an advance in our understanding of sex-related differences in the function of the immune system.

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