Introduction: Sex as a Biological Variable in Immunity

A decade ago, I published a seminal review with Katie Flanagan in Nature Reviews Immunology entitled “Sex differences in immune responses” 1, making the case that sex is a fundamental biological variable shaping innate and adaptive immunity across the lifespan and across diverse species, highlighting that these differences are dynamic and evolutionarily conserved. That 2016 paper synthesized the hormonal and genetic mechanisms underlying immunological differences between males and females, documented their consequences for autoimmune disease, infectious disease, malignancy, and vaccine responses, and issued a call that the field of immunology, which at the time ranked last among 10 biological disciplines in reporting the sex of animal or human subjects in published research 2, needed to take sex seriously as a variable in experimental design, analysis, and clinical translation. The paper arrived at a pivotal moment, coinciding with the 2016 formal implementation of the NIH policy mandating the consideration of sex as a biological variable in preclinical research 3. A decade later this special issue of Immunological Reviews allows for us to highlight the transformation that has occurred. What was once a field of study on the periphery of immunology has become more central in defining immunological mechanisms of health and disease. Some of the mechanisms that were broadly outlined in 2016 have since been elaborated. For example, the epigenetic architecture of X-chromosome inactivation and escape has been mapped in immune cells, the pleiotropic and context-dependent effects of estrogens, androgens, and progesterone on virtually every arm of immunity has been established, the role of the microbiome in sex differences in the immune phenotype, and the sex-differential gene expression programs that operate within individual immune cell populations to mediate responses to disease states and treatments have been documented. These mechanistic advances have been matched by a growing clinical and epidemiological literature demonstrating that immunological sex differences have consequences across a diverse range of human diseases. The field has grown substantially, and the present collection reflects both the depth and the breadth of that growth. This special issue of Immunological Reviews, titled Sex Differences in Immunity, brings together 15 reviews that collectively advance our understanding of the biological mechanisms that cause sex differences in immunity with implications for a broad spectrum of human diseases. The contributors span genetics, immunology, infectious disease, pulmonology, oncology, autoimmunity, transplantation medicine, neuroscience, and reproductive biology, reflecting the field's recognition that sex as a biological variable is fundamental in immunology research with implications for medicine and public health. These papers collectively confirm that ignoring sex in immunological research is not only scientifically incorrect but has consequences for the health of patients across the lifespan and among populations in diverse regions of the world. The issue opens with a foundational paper by Radovanovic, Wynalda, and Anguera 4, which examines the X chromosome as a primary driver of sex differences in immunity, reviewing the epigenetic regulation of escape from X-chromosome inactivation in immune cells and the dosage-sensitive X-linked immune genes that contribute to female-biased autoimmunity and heightened antiviral responses. The second cluster of papers bridges foundational mechanisms with disease outcomes by examining how biological sex shapes immunity in specific tissues, metabolic states, and physiological contexts. Vijayakumar and colleagues 5 address the immunological consequences of obesity through a sex differences lens, detailing how males and females differ in patterns of adipose tissue inflammation, adipocytokine production, and gut microbiota composition, and how these differences translate into sex-divergent risks for infection, autoimmunity, cancer, and cardiometabolic disease. Saminathan and colleagues 6 present an innovative framework proposing that sex-biased immunometabolism, encompassing purine metabolism, glycolytic remodeling, lipid sensing, and mitochondrial stress pathways, creates a mechanistic bridge between biological sex and neuroinflammatory disease risk. Moving to organ-specific immunity, Puttur and Lloyd 7 review how sex shapes immune defenses in the lung, a tissue in constant contact with the external environment, highlighting the interplay of gonadal steroids, genetics, and environmental exposures in impacting pulmonary immune responses and their relevance for infection, asthma, cancer, and autoimmune lung disease. The third section examines sex differences across a broad spectrum of infectious diseases. Pujantell and Altfeld 8 address HIV-1, reviewing how X and Y chromosome-linked genes and gonadal steroid hormones modulate antiviral immune pathways and shape sex differences in disease progression, immune activation, and responses to antiretroviral therapy. Gupta, Klein, and Bishai 9 examine tuberculosis, which is still the world's leading infectious cause of death, documenting the male predominance in incidence, disease severity, and treatment failure, and interrogating the respective contributions of gonadal steroids, sex chromosomes, and immune function to these disparities. Ramirez Finn and Ingersoll 10 focus on mucosal bacterial infection in the urinary tract, where sex differences in epithelial-bacterial interactions and innate immune sensing at mucosal surfaces underlie sex differences in the incidence of urinary tract infections. Honecker, Hansen, and Lotter 11 broaden the scope to parasitic diseases of global importance, including leishmaniasis, Chagas disease, amebiasis, schistosomiasis, and malaria, with synthesis of traditional measures of immune function with emerging single-cell transcriptomic data to characterize sex differences in innate and adaptive cellular responses that influence parasitic disease outcomes. Grewe, Zoran, and Addo 12 pivot from infection to prevention, reviewing clinical evidence for sex differences in immune responses to viral vector vaccines, including replication-competent and replication-deficient platforms, with a detailed discussion of the mechanistic basis for sex differences and their implications for sex-informed vaccine design and dosing. Closing this section, Parish and Klein 13 examine the immunology of pregnancy as a distinct biological state, reviewing how respiratory viral infections during gestation drive maternal immune activation that can have lasting neurodevelopmental consequences in offspring, particularly in males, suggesting that sex differences in immunity and disease pathogenesis have in utero origins. The final group of papers moves toward applied and translational questions, examining sex differences in the context of immune-mediated diseases, cancer, and clinical medicine. Bustillos and colleagues 14 open this section by reviewing how sex hormonal and sex chromosomal factors interact across the lifespan to shape both anti-cancer immunity and autoimmunity, highlighting that gonadal steroid concentrations are not static and sex chromosomal complement can change somatically (e.g., loss of chromosome Y) with immunological consequences that start during puberty and continue through older age. Dunn, Alvarez-Sanchez, and Steinman 15 then address the female predominance of multiple sclerosis (MS) with novel consideration of how early life exposure to Epstein–Barr virus (EBV) could result in sex differences in presentation of MS. They review evidence that EBV seroprevalence, infectious mononucleosis incidence, cross-reactive autoantibody production, and the latency dynamics of EBV-infected B cells all differ by sex in ways that might explain how MS disproportionately affects women. Krieghoff-Henning and colleagues 16 examine cancer immunotherapy, presenting clinical and mechanistic evidence that males and females respond differently to immune checkpoint blockade, particularly in the context of non-small cell lung cancer and melanoma. They use data to inform recommendations for sex-stratified trial designs capable of generating actionable, sex-informed treatment strategies. McKernan, Henriquez Pilier, and Newcomb 17 address asthma, where sex disparities in prevalence shift during puberty and reproductive ages, reviewing the divergent roles of androgens and estrogens in regulating type 2 and neutrophilic airway inflammation and pointing toward the promise of sex-personalized therapeutic approaches. Perry and Sen 18 close the issue with a comprehensive review of sex differences in transplant immunology, detailing how sex chromosomal, gonadal steroid, and pregnancy-related alloimmunization factors interact with age to shape graft rejection risk, immunosuppressive drug metabolism, and infection susceptibility. These 15 contributions highlight several cross-cutting themes that broadly define the current state of the field with recommendations for its future. Collectively, this special issue shows that sex differences in immunity arise from the combinatorial effects of sex chromosome complement, gonadal steroids, age-related hormonal transitions, and environmental interactions, with no single factor providing a complete account for sex differences in all diseases. Second, sex differences in immunity are contextual in which the same biological mechanisms that confer resistance to infection or cancer may simultaneously confer susceptibility to autoimmunity. Third, particularly among women, the immunological phenotype can change over the life course, including after puberty, during pregnancy, and following menopause, which impacts disease pathogenesis, prognosis, and responses to treatments. Fourth, virtually every paper in this collection notes a persistent gap in sex-disaggregated data, whether in clinical trials, epidemiological cohorts, or preclinical models that remains pervasive in the published literature and therefore limits mechanistic insights and therapeutic translation. Finally, and perhaps most importantly, the authors collectively articulate a vision in which understanding sex differences is not an end in itself but a path toward precision medicine, including sex-informed vaccine dosing, sex-specific immunosuppressive regimens, sex-stratified cancer immunotherapy, and targeted interventions for diseases whose sex-biased burden affects global public health. Together, we have tried to synthesize current knowledge and catalyse the next decade of sex-informed immunological research. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.