Sex Differences

Sex Differences in Immunity

Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed that sex differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains to be learned about the mechanisms underlying associations between sex differences and immune-mediated conditions. A growing body of experimental data has made significant inroads into understanding sex-influenced immune responses. As physicians seek to provide more targeted patient care, it is critical to understand how sex-defining factors (e.g., chromosomes, gonadal hormones) alter immune responses in health and disease. In this review, we highlight recent insights into sex differences in autoimmunity; virus infection, specifically severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; and cancer immunotherapy. A deeper understanding of underlying mechanisms will allow the development of a sex-based approach to disease screening and treatment. Read the review: Wilkinson et al, Annual Review of Immunology, 2022

Schematic representation of how sex differences, contributed by sex chromosomes and gonadal hormones, alter immune responses in autoimmunity, viral infection, and cancer. Growing evidence points to diverse immunomodulatory roles in both innate and adaptive arms, contributing to sex biases seen at the population level.
Schematic of mechanisms underlying sex-related differences in immunity. Sex chromosome complement (e.g., 46XX or 46XY), gonads (ovaries or testes), and sex steroids (e.g., estrogens or androgens) contribute to sex differences in the immune response. The X and Y chromosomes differ in gene content, with many immune-related genes located on the X chromosome. Moreover, the degree to which a subset of X chromosome genes is expressed differs between cells, tissue types, and individuals, which adds complexity to chromosomal contributions to sex differences. Sex steroids influence lymphocyte development, proliferation, and activation. Collectively, these sex-specific factors modulate innate and adaptive immunity and subsequently alter outcomes of autoimmunity, viral infection, and cancer immunotherapy. Abbreviations: AIRE, autoimmune regulator; COVID-19, coronavirus disease 2019; ICI, immune checkpoint inhibitor; IFN, interferon; IrAE, immune-related adverse event; pDC, plasmacytoid dendritic cell; TCR, T cell receptor; TLR7, Toll-like receptor 7.

The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences

Viral infection outcomes are sex biased, with males generally more susceptible than females. Paradoxically, the numbers of antiviral natural killer (NK) cells are increased in males. We demonstrated that while numbers of NK cells are increased in male mice, they display decreased effector function compared to females in mice and humans. These differences were not solely dependent on gonadal hormones, because they persisted in gonadectomized mice. Kdm6a (which encodes the protein UTX), an epigenetic regulator that escapes X inactivation, was lower in male NK cells, while NK cell-intrinsic UTX deficiency in female mice increased NK cell numbers and reduced effector responses. Furthermore, mice with NK cell-intrinsic UTX deficiency showed increased lethality to mouse cytomegalovirus. Integrative multi-omics analysis revealed a critical role for UTX in regulating chromatin accessibility and gene expression critical for NK cell homeostasis and effector function. Collectively, these data implicate UTX as a critical molecular determinant of sex differences in NK cells. Read the paper: Cheng et al, Nature Immunology, 2023

Schematic representation of the role that epigenetic regulator UTX, an escapee of X chromosome inactivation, potentiates natural killer (NK) cell responses through chromatin remodeling at key effector loci.
Schematic representation of how differential UTX expression levels underlie sexual dimorphism in NK cell composition and function (left). Diagram of how UTX may be regulating gene programs involved in NK cell numbers and effector function during homeostasis and viral infection (right).

Sex Matters: Hormonal and Chromosomal Determinants
of Autoimmunity and Anti-Cancer Immunity Across
the Lifespan

Sex plays a key role in shaping both anti‐cancer immunity and autoimmunity. Biological factors underlying sexual dimorphism have now been identified in multiple aspects of anti‐cancer immunity and autoimmunity. These factors include sex differences in hormone levels, chromosome complement, and expression of the long non‐coding RNA XIST. In this review, we discuss recent advances delineating how these differences alter immune responses against cancer and autoimmune responses against healthy tissues. Moreover, we now understand that hormone levels change (e.g., in mini‐puberty, menopause, and andropause) and that somatic alterations in chromosomal complement accumulate (e.g., loss of Y [LOY] chromosome) across the lifespan. We also include here a discussion of how these changes affect anti‐cancer immunity and autoimmunity across a lifetime. These recent advances will set the stage for identifying immunotherapeutic approaches that optimize anti‐cancer immunity while controlling the autoimmune responses. Read our invited review: Bustillos et al, Immunological Reviews, 2026

Schematic representation of long non-coding RNA XIST's activities beyond its canonical role of initiating and spreading X chromosome inactivation, acting as both a regulator and target of immune responses.
Canonical and noncanonical functions of Xist. (A) Canonical Xist function of coating the Xi and enacting the process of XCI. Absence of Xist has been shown to lead to increased autoimmunity through increased TLR7 expression from the Xi. (B) Noncanonical functions of Xist. Xist has been shown to dampen autosomal gene expression and function as a TLR7 agonist to promote incidence of autoimmunity. Xist can also form RNP complexes (with proteins such as Spen, PRC1, DHX9, and SSB) that are antigenic and are targeted by autoantibodies in systemic autoimmunity.