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Mechanisms and consequences of sex differences in immune responses

Nature Reviews Nephrology volume 20, pages 37–55 (2024)Cite this article

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Abstract

Biological sex differences refer to differences between males and females caused by the sex chromosome complement (that is, XY or XX), reproductive tissues (that is, the presence of testes or ovaries), and concentrations of sex steroids (that is, testosterone or oestrogens and progesterone). Although these sex differences are binary for most human individuals and mice, transgender individuals receiving hormone therapy, individuals with genetic syndromes (for example, Klinefelter and Turner syndromes) and people with disorders of sexual development reflect the diversity in sex-based biology. The broad distribution of sex steroid hormone receptors across diverse cell types and the differential expression of X-linked and autosomal genes means that sex is a biological variable that can affect the function of all physiological systems, including the immune system. Sex differences in immune cell function and immune responses to foreign and self antigens affect the development and outcome of diverse diseases and immune responses.

Key points

  • Biological sex refers to the differences between males and females caused by a differential sex chromosome complement (most commonly XX or XY in mammals), whereas gender refers to socially constructed norms that determine the roles, relationships and positional power of men and women across their lifetime.

  • Current evidence supports the notion that sex chromosomes and gonadal hormones modulate the number and functions of immune cells.

  • There are well characterized sex differences in the innate and adaptive immune response; there is strong evidence that type I and type II interferon signalling and humoral responses are greater in females than in males across diverse species.

  • Sex differences in both innate and adaptive immunity contribute to the increased prevalence of autoimmunity in females and increase the propensity of females to reject their organs post-transplantation.

  • Sex differences research is uncovering novel therapeutic pathways that could be targeted to improve disease outcomes in all sexes.

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Fig. 1: Mechanisms underlying sex differences in the production of type I interferon.
Fig. 2: Sex differences in the production of IFNγ by T cells.
Fig. 3: Sex differences in the balance of IL-17-producing T cells and T regulatory cells regulate sex differences in experimental hypertension.

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Acknowledgements

The authors thank K. L. Sandberg, Georgetown University, DC, USA, for critical review of the section on hypertension during the revisions process. S.E.D.’s work is supported by a Canadian Institutes of Health Research (CIHR) Sex and Gender Chair in Immunity and operating grants from CIHR, MS Canada and the BranchOut Foundation. S.L.K’s work is supported by the Johns Hopkins Specialized Center of Research Excellence in Sex Differences (U54AG062333).

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Authors and Affiliations

  1. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Shannon E. Dunn

  2. Women’s College Research Institute, Women’s College Hospital, Toronto, Ontario, Canada

    Shannon E. Dunn

  3. Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA

    Whitney A. Perry

  4. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Sabra L. Klein

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Dunn, S.E., Perry, W.A. & Klein, S.L. Mechanisms and consequences of sex differences in immune responses. Nat Rev Nephrol 20, 37–55 (2024). https://doi.org/10.1038/s41581-023-00787-w

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