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Sex differences in immune responses

Key Points

  • Sex is a biological variable that affects the functions of the immune system.

  • Sex differences occur in both innate and adaptive immune responses and are evolutionarily conserved across diverse species.

  • Sex differences in immune responses change throughout life and are influenced by both the age and reproductive status of an individual.

  • Sex chromosome genes and sex hormones, including oestrogens, progesterone and androgens, contribute to the differential regulation of immune responses between the sexes.

  • Environmental factors, including nutrition status and the composition of the microbiome, also alter the development and functioning of the immune system differently in males and females.

  • Sex differences in immune responses result in differential susceptibility of males and females to autoimmune diseases, malignancies and infectious diseases, as well as affecting the outcome of vaccination.

Abstract

Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

Main

Sex is a biological variable that affects immune responses to both self and foreign antigens (for example, those from fungi, viruses, bacteria, parasites and allergens). The sex of an individual is defined by the differential organization of chromosomes, reproductive organs, and sex steroid levels; it is distinct from gender, which includes behaviours and activities that are determined by society or culture in humans. Male and female differences in immunological responses may be influenced by both sex and gender, with sex contributing to physiological and anatomical differences that influence exposure, recognition, clearance, and even transmission of microorganisms. By contrast, gender may reflect behaviours that influence exposure to microorganisms, access to healthcare or health-seeking behaviours that affect the course of infection. Although we acknowledge that both sex and gender influence the immune response, the focus of this Review will be on the biological factors that influence immunological differences between the sexes. Despite a growing body of literature illustrating sex-based differences in immune responses, immunology ranks the lowest of ten biological disciplines for reporting the sex of animal or human subjects in published papers, with fewer than 10% of articles analysing data by sex1. The field of sex-based biology is undergoing a revolution, in which research funding agencies and journals have launched policies to promote greater consideration, reporting and analyses of sex and gender in the biomedical sciences in an effort to improve rigour and reproducibility (Box 1).

It is increasingly important to acknowledge sex differences in immune responses when we consider the marked differences seen between males in females in various diseases. For instance, 80% of autoimmune disease occurs in females, women with acute HIV infection have 40% less viral RNA in their blood than men, men show an almost twofold higher risk of death from malignant cancer than women and antibody responses to seasonal influenza vaccines are consistently at least twice as strong in women than men. Generally, adult females mount stronger innate and adaptive immune responses than males. This results in faster clearance of pathogens and greater vaccine efficacy in females than in males but also contributes to their increased susceptibility to inflammatory and autoimmune diseases. In this Review, we explain how these immunological differences between the sexes reflect hormonal, genetic and environmental effects on the immune system that can change throughout life in humans.

Phylogeny of sex differences in immunity

Mounting immune responses that are necessary for the recognition, response and clearance of pathogens requires metabolic resources that might otherwise be used for other biological processes, such as growth, maintenance of secondary sex characteristics and reproduction. Trade-offs are likely to exist for life strategies that affect survival and reproduction2. Several theories posit that increased pathogen loads and reduced immune function among males are an adverse side effect of positive selection for other traits or characteristics that increase reproductive success and survival2. Sex differences in immune responses have evolved in diverse species ranging from insects to lizards, birds and mammals; in all of these species, both innate and adaptive immune responses are typically lower in males than in females (Table 1). In Drosophila melanogaster, for example, many of the genes that encode for innate signalling proteins are found on the X chromosome and show sex-specific induction following fungal or bacterial infection3,4. In lizards, the phagocytic activity of macrophages is greater in females than in males owing to the suppressive effects of androgens on male macrophage activity5. In birds, females exhibit higher antibody and cell-mediated immune responses to immune challenges, and these effects are often most pronounced during the mating season when male testosterone concentrations are highest6,7.

Table 1 Sex differences in immune responses in different species

Sex differences in innate immunity in mammals

Among mammals, males and females differ in their innate immune responses, which suggests that some sex differences may be germline encoded (Table 2). For example, innate detection of nucleic acids by pattern recognition receptors (PRRs) differs between the sexes. The Toll-like receptor 7 (TLR7) gene, encoded on the X chromosome, may escape X inactivation resulting in higher expression levels of TLR7 in females than males8. Exposure of peripheral blood mononuclear cells (PBMCs) to TLR7 ligands in vitro causes higher production of interferon-α (IFNα) in cells from women than from men9; in addition, plasmacytoid dendritic cells (pDCs) from female humans and mice have higher basal levels of IFN regulatory factor 5 (IRF5) and IFNα production following TLR7 ligand stimulation10. Transcriptional regulation of IRF5 in female mice is under the control of signalling through oestrogen receptor-α (ERα)10. Stimulation of DCs with CpG, a TLR9 ligand, results in no sex bias in IFNα production9. Transcriptional analyses reveal sex differences in the expression of genes along TLR pathways and induction of type I IFN responses. Following either vaccination in adult humans or virus challenge in adult rats, the expression of TLR-pathway and pro-inflammatory genes (for example, TLR7, myeloid differentiation primary response gene 88 (MYD88), retinoic acid inducible gene-I (RIGI), IRF7, IFNB, Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT3), nuclear factor-κB (NFKB), IFNG and tumour necrosis factor (TNF)) is higher in female than male PBMCs from humans and tissues from rats11,12. Putative androgen response elements (AREs) and oestrogen response elements (EREs) are present in the promoters of several innate immunity genes, suggesting that sex steroids may directly cause dimorphic innate immune responses12.

Table 2 Sex differences in innate and adaptive immune responses in adults*

The production of cytokines and chemokines by innate immune cells also differs between the sexes. Activation of TLR9 with viral or synthetic ligands in PBMCs from human males results in greater interleukin-10 (IL-10) production compared with PBMCs from females, which is positively correlated with androgen concentration in males13. PBMCs from human males produce more TNF than PBMCs from females following lipopolysaccharide (LPS) stimulation14,15. Neutrophils from human males express higher levels of TLR4 and produce more TNF than female neutrophils both constitutively and following activation with LPS16. Peritoneal macrophages from male mice express higher levels of TLR4 and produce more CXC-chemokine ligand 10 (CXCL10) following LPS stimulation than macrophages from females17. Peritoneal macrophages isolated from female rodents produce higher levels of anti-inflammatory prostanoids than male-derived cells following LPS treatment17. Because TLR4 expression is greater on immune cells from males than females, stimulation with LPS results in greater pro-inflammatory cytokine production by male immune cells, which can be reversed by removal of androgens in male rodents18. By contrast, higher expression of TLR7 in immune cells from females compared with males seems to cause greater cytokine production by female immune cells and is regulated by sex chromosome expression. The sex differential expression of PRRs is crucial for interpreting sex-specific activity of innate immune cells following stimulation.

The number and activity of cells associated with innate immunity differ between the sexes. Males have higher natural killer (NK) cell frequencies than females19. The phagocytic activity of neutrophils and macrophages is higher in females than males20. Antigen-presenting cells (APCs) from females are more efficient at presenting peptides than APCs from males21. Finally, sex differences are also seen in innate lymphoid cells (ILCs), which are innate-like lymphocytes that regulate an array of tissue immune responses through the production of effector cytokines. Dysregulation of ILCs is linked to the development of autoimmune diseases, and females reportedly have reduced numbers of type 2 ILCs, which is hypothesized to contribute to their increased susceptibility to demyelination in a mouse model of multiple sclerosis22.

Sex differences in adaptive immunity in mammals

Sex influences multiple aspects of adaptive immunity (Fig. 1; Table 2). The thymus plays a pivotal part in the development of the adaptive immune system by producing the peripheral T cell pool. Early in life, male rats have larger thymuses, greater thymocyte counts and differential distribution of thymocyte subsets compared with female rats23,24.

Figure 1: Changes in immune responses in human males and females over the life course.
figure1

Multiple immunological factors vary between the sexes throughout the course of life. For certain factors (for example, pro-inflammatory responses), the sex differences change at puberty and then wane in later life suggesting hormonal effects. For other factors the sex difference remains constant from birth to old age (for example, higher numbers of CD4+ T cells and CD4/CD8 T cell ratios in females). The paucity of studies in this area is notable, particularly in utero sex differences in which results are conflicting. IL-10, interleukin-10; NK, natural killer; Treg, regulatory T.

PowerPoint slide

Among adult humans, sex differences in lymphocyte subsets — including B cells, CD4+ T cells and CD8+ T cells — are described for multiple ethnic groups including Europeans, Asians, and Africans. Females (both children and adults) have higher CD4+ T cell counts and higher CD4/CD8 ratios than age-matched males19,25,26,27; whereas males have higher CD8+ T cell frequencies25,26,27. Following in vitro stimulation of PBMCs, women have higher numbers of activated CD4+ T cells and CD8+ T cells and proliferating T cells in peripheral blood compared to men19,28. Transcriptional analyses indicate greater cytotoxic T cell activity in adult females, with PMA–ionomycin-stimulated T cells from women upregulating more antiviral genes (such as IFNG, RIGI, SPINK5, OAS1 and IFI6) and pro-inflammatory genes (for example, IL12RB2, IL1F5, CXC3CL1, CXCL2 and IL16) compared with T cells isolated from men29. Notably, half of the activated genes in female T cells have EREs in their promoters29.

The activity and distribution of CD4+ T cell subsets differ between the sexes. Adult female mice produce higher levels of T helper 1 (TH1)-type cytokines (for example, IFNγ) than males, at least following parasitic infections, such as Leishmania major and Plasmodium chabaudi, in which females are better protected30. Polyclonal activation of human PBMCs with the mitogen phytohaemagglutinin (PHA) results in higher production of TH2-type cytokines, including IL-4 and IL-10 in female PBMCs than in male PBMCs31. The TH1–TH2 dichotomy in males and females may not always hold true in humans. Naive CD4+ T cells from human females preferentially produce IFNγ upon stimulation, whereas naive T cells from males produce more IL-17 (Ref. 32). Expression of IL-17A is higher in males29 or females28, depending on the stimulation and purity of the T cell population. Mouse studies investigating sex differences in regulatory T (Treg) cells describe contradictory results regarding organ-specific Treg cell frequencies in various diseases, whereas human studies suggest there are higher numbers of Treg cells in healthy adult males compared with females33.

Regardless of age, females tend to show greater antibody responses than males, higher basal immunoglobulin levels and higher B cell numbers19,34,35. Global analysis of B cell gene-expression signatures reveal that the majority of genes differentially expressed between the sexes are significantly upregulated in B cells from females compared with males36.

Genetic mediators

Sex chromosomes. Many genes on the X chromosome regulate immune function and play an important role in modulating sex differences in the development of immune-related diseases37 (Box 2). These genes code for proteins ranging from PRRs (for example, TLR7 and TLR8) to cytokine receptors (for example, IL2RG and IL13RA2) and transcriptional factors (for example, FOXP3). The Y chromosome also contains numerous regulatory response genes, and Y chromosome polymorphisms affect sex-dependent susceptibility to viral infection38.

The SRY gene on the Y chromosome causes testes formation and testosterone synthesis, leading to male phenotypic development, whereas the absence of SRY expression results in ovaries and female-typic development. The 'four core genotypes' (FCG) mouse model was developed to investigate the impact of sex chromosomes (XX versus XY) and gonadal type (testes versus ovaries) on phenotypes. Deletion of Sry from the Y chromosome results in XY minus (XY) FCG mice that are gonadal females (that is, with ovaries). Insertion of the Sry transgene onto an autosome in XX or XY FCG mice (XXSry and XYSry) results in gonadal males (that is, with testes). Depletion of gonadal steroids by gonadectomy of FCG mice unmasks effects of sex chromosome complement on multiple functions, including susceptibility to autoimmune disease and viral infection39,40. In experimental autoimmune encephalitis (EAE) and lupus, for example, the presence of the XX sex chromosome complement worsens disease progression, relative to that in the XY mice, and results in decreased production of IL-4, IL-5 and IL-13, but increased IL-13Rα2 expression on DCs39.

Klinefelter and Turner syndromes are two inherited disorders that further exemplify the effects of the X chromosome on immunity. Klinefelter syndrome occurs when males have an extra X chromosome, resulting in low testosterone, increased gonadotrophins and elevated oestrogen concentrations. Immunologically, men with Klinefelter syndrome respond more like females, with higher immunoglobulin concentrations, CD4+ T cell numbers, CD4/CD8 T cell ratios and B cell numbers than XY male controls41. The immunological effects of Klinefelter syndrome are reversed by testosterone therapy41, illustrating that both sex chromosomes and sex steroids regulate immune responses. By contrast, women with Turner syndrome (that is, who have only one X chromosome (X0) or have major X chromosome deletions42) have lower IgG and IgM levels and lower T cell and B cell levels compared to XX females43. Both patients with Klinefelter syndrome and patients with Turner syndrome show increased development of autoimmune disease, pointing to a major role for the X chromosome in influencing susceptibility to autoimmunity42.

MicroRNAs and long non-coding RNA. Much of the mammalian genome encodes for transcripts that are not translated into proteins, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Despite the fact that male and female invertebrates and higher organisms differentially express miRNAs, few studies have addressed the role of miRNAs in sex differences in diseases44. The X chromosome contains 10% of the 800 miRNAs in the human genome, whereas the Y chromosome only contains 2 miRNAs45. MiRNAs — including miRNA-18 and miRNA-19, which are encoded on the X chromosome — play a role in sex differences in immune responses46. MicroRNA expression can be under sex hormone control47. The high density of miRNAs on the X chromosome means that females may express more owing to incomplete X inactivation (Box 2), further contributing to sex differences in susceptibility to certain diseases.

The lncRNAs play a vital role in the regulation of multiple immunological processes, including transcriptional regulation of innate and adaptive immunity48 and as a catalyst of X inactivation in a manner that has been shown to be sex-differential49.

Genetic polymorphisms. Polymorphisms or variability in sex chromosome and autosomal genes encoding immunological proteins can have sex-differential effects on immunity. For example, sex-based differences in HLA alleles and genes that encode for IL-4, IL-10 and the IL-12 receptor, have each been associated with differential antibody responses to vaccines against measles, mumps, hepatitis A, tetanus and diphtheria in children and adults11. Whether sex-based differences in the expression of gene variants are caused by differential selection pressures acting on each sex, hormone-dependent effects, or epigenetic mechanisms remain to be determined but, because these differences are apparent early in life and remain over the life course, genetic as opposed to hormonal mechanisms are likely to be involved50.

Hormonal mediators

Oestradiol. Levels of oestrogen, for example, 17β-oestradiol (E2), are variable during the menstrual cycle, high during pregnancy and low after menopause in females. ERs are expressed in various lymphoid tissue cells, in lymphocytes, macrophages, and DCs. The two ER subtypes for classical oestrogen signalling, ERα and ERβ, exhibit differential expression among immune cell subsets; ERα is highly expressed in T cells and ERβ is upregulated in B cells51. Non-classical ER signalling also occurs in immune cells, enabling protein–protein interactions between ERs and ERE-independent transcription factors, including NF-κB, specific protein 1 (SP1) and activator protein 1 (AP-1)52. Differential effects of oestrogens on immune function reflect not only oestrogen concentration but also the density, distribution and type of ERs in immune cells.

E2 affects many aspects of innate immunity (Table 3), including the functional activity of innate immune cells that influence downstream adaptive immune responses. Treatment of either humans or mice with E2 increases neutrophil numbers in the blood and lungs, respectively53,54. Exposure of NK cells to E2 in vitro enhances production of IFNγ and overall cytotoxicity55, but also downregulates expression of NK cell surface activation markers and FAS ligand (FASL), and reduces their secretion of granzyme B in mice56. E2 has bipotential effects on monocytes and macrophages derived from humans, with low doses enhancing the production of pro-inflammatory cytokines (such as IL-1, IL-6 and TNF) and high concentrations reducing their production of these cytokines57. E2 also enhances the expression of PRRs, including TLR4, on the surface of peritoneal macrophages in rodents58. In vitro E2 exposure facilitates the differentiation of bone marrow precursor cells into functional CD11c+ DCs59 and increases the synthesis of CXCL8 and CC-chemokine ligand 2 (CCL2) by immature DCs in mice60. Treatment of ovariectomized mice with physiological doses of E2 increases production of pro-inflammatory cytokines by CD11c+ DCs61,62. E2 acts primarily through ERα, not ERβ, to regulate DC differentiation in mice59. In response to granulocyte–macrophage colony-stimulating factor (GM-CSF) in human monocyte cell systems, E2 promotes differentiation of monocytes into inflammatory DCs, which show increased production of IFNα and pro-inflammatory cytokines, increased TLR7 and TLR9 signalling, and greater internalization and presentation of antigen to naive T cells63. This is most likely to contribute to the greater type I IFN activity seen in immune cells from females than in males.

Table 3 Effects of sex steroid hormones on innate and adaptive immunity

E2 enhances both cell-mediated and humoral immune responses (Table 3). Generally, low E2 concentrations promote TH1-type responses and cell-mediated immunity, whereas high E2 concentrations augment TH2-type responses and humoral immunity in diverse species and cell culture systems64. Binding of E2 to ERs increases Ifng transcription via EREs in the promoter region of the Ifng gene65. Low dose E2 also upregulates mitogen activated protein kinase (MAPK), T-bet, and select miRNAs to increase production of IFNγ by T cells, an effect reversed by the ER antagonist ICI 182,780 in murine studies66,67,68. E2 regulates pro-inflammatory responses that are transcriptionally mediated by NF-κB through a negative feedback and/or transrepressive interaction with NF-κB64.

Exogenous E2 enhances the expansion of Treg cell populations in mice and healthy women and, in vitro, E2 increases the number of Treg cells generated from PBMCs69,70. Treatment of mice with high doses of E2 decreases IL-17 production by TH17 cells71, whereas ovariectomy of female mice increases TH17 cell numbers and IL-17 production72. E2 at physiological concentrations also stimulates humoral responses to infection73. Numbers of antibody-secreting cells and antibody levels are highest before ovulation in females73. Oestrogen also induces somatic hypermutation and class switch recombination in B cells via the upregulation of activation-induced deaminase74.

Progesterone. Progesterone (P4) is produced by the corpus luteum during the menstrual cycle and at high levels by the placenta during pregnancy. P4 signals through the progesterone receptor and to a lesser extent, through glucocorticoid and mineralocorticoid receptors. progesterone receptors are present on many different immune cell types, including NK cells, macrophages, DCs, and T cells75.

P4 has broad anti-inflammatory effects (Table 3). P4-exposed macrophages and DCs have a lower state of activation and produce lower amounts of IL-1β and TNF compared with untreated cells76,77. P4 treatment of mouse bone marrow-derived macrophages induces the expression of FIZZ1 and YM1, both markers of alternatively activated macrophages, and reduces production of inducible nitric oxide synthase (iNOS) and nitric oxide (NO)78. TLR and the NF-κB pathways can also be antagonized by the action of P4 (Refs 76,79). Treatment of human NK cells with P4 reduces activation and production of IFNγ via caspase-dependent apoptosis80. Progesterone can promote skewing of CD4+ T cell responses from TH1-type towards TH2-type responses, as characterized by increased IL-4, IL-5, and IL-10 production81. When cord blood cells are treated with P4, the percentage of FOXP3+ Treg cells increases, while TH17 cell frequencies decline82. Whether P4 contributes directly to male–female differences in the skewing of CD4+ T cell responses requires consideration.

Androgens. Androgens, including dihydrotestosterone (DHT) and testosterone, occur in higher concentrations in post-pubertal men than women, and they generally suppress immune cell activity30 (Table 3). Exposure to testosterone in vivo reduces NK cell activity in mice83. Surface expression of TLR4 on macrophages is reduced by exposure to testosterone both in vitro and in vivo, driving increased susceptibility to endotoxic shock following gonadectomy of male mice18. Testosterone reduces the synthesis of TNF, iNOS and NO by macrophages84. Testosterone and DHT increase IL-10 and transforming growth factor-β (TGFβ) synthesis, causing increased anti-inflammatory responses via androgen receptor signalling84,85. Androgens also suppress pro-inflammatory responses by reducing extracellular signal-regulated kinases and leukotriene formation in neutrophils86.

Men with androgen deficiencies have higher concentrations of inflammatory cytokines (for example, IL-1β, IL-2 and TNF), antibody titers and CD4/CD8 T cell ratios than men with normal testosterone levels87,88,89,90. Men treated with a gonadotropin-releasing hormone antagonist, which significantly reduces testosterone levels, have lower peripheral blood Treg cell counts and higher NK cell counts compared with placebo-treated men or men treated with both the gonadotropin-releasing hormone antagonist and exogenous testosterone91. Castrated male mice have higher numbers of CD4+ and CD8+ T cells92 and higher numbers of macrophages and antigen-specific CD8+ T cells following viral infection than gonadally intact males93. Treatment of female mice with testosterone inhibits secretion of IFNγ by natural killer T cells94.

The immunosuppressive effects of androgens may reflect the inhibitory effects of androgen receptor signalling on transcriptional factors for pro-inflammatory and antiviral cytokines95. Androgens also enhance the expression of peroxisome proliferator-activated receptor-α (PPARα) in T cells by engaging AREs in the promoter of the PPARα gene, which repress the activity of NF-κB and JUN to control inflammation96. Taken together, these studies illustrate that sex steroids are potent regulators of immune responses.

Environmental mediators

Although genes and hormones are the most well characterized mediators of sex differences in immune responses, environmental factors can also modulate the functioning of the immune system differentially between males and females.

Nutrition. The nutritional environment of the fetus can have differential effects depending on its sex. Maternal micronutrient supplementation during pregnancy in a Gambian placebo-controlled study reported sex differences in CpG methylation of genes involved in immunity and defence against infection (for example, genes encoding CD4, defensins and genes associated with IFN signalling), and female fetuses were most affected in the supplemented group whereas males were most affected in the non-supplemented group97. The study demonstrates that sex-differential developmental trajectories commence in utero and persist to 9 months of age, indicating long-term epigenetic reprogramming in relation to nutrition during pregnancy. A high-fat diet also enhances, whereas prenatal exposure to famine reduces, placental gene expression and DNA hypomethylation to a greater extent in female than in male fetuses98. Several studies also suggest that the immunomodulatory effects of breast milk may benefit infant females more than males, with breastfeeding reducing the risk of neonatal respiratory tract infection in female but not male infants99.

There is accumulating evidence that micronutrients act differently in males and females. Perinatal and postnatal vitamin B, vitamin C and vitamin E supplements are associated with a 32% reduction in mortality among females but not males in a randomized placebo-controlled trial of Tanzanian mothers infected with HIV100. Studies conducted in African and Asian infants suggest that females may benefit more than males from maternal micronutrient supplements101,102. Vitamin A supplementation (VAS), given with measles vaccination to children between 6 and 23 months of age, have sex differential immunomodulatory effects compared to a placebo, including decreased leukocyte subsets in males, and increased numbers of leukocytes and IFNγ production by ex vivo stimulated cells from females103.

Microbiota. A perturbed microbiome — referred to as dysbiosis — contributes to various disease processes including inflammation and diabetes. Sex influences the host microbiome outside of the reproductive tract, which probably involves sex steroid hormones104,105. During early life, sex does not influence the microbiome composition. Deep sequencing of colonic contents in pre-pubescent mice report no sex difference in bacterial community composition, suggesting that sex does not influence the microbiome in this age group106. A number of mouse studies, however, show sex differences in host gene expression in the gastrointestinal tract before puberty, demonstrating that sex-specific gene regulation occurs even in the absence of high levels of circulating sex hormones106. After puberty, female rodents have lower frequencies of Bacteroidetes than males104,105.

In a mouse model of spontaneous type 1 diabetes, adoptive transfer of gut commensals from male mice into females resulted in systemic hormonal changes and protected against disease104,105. Similar to what is seen in mice, the human female microbiome is less abundant in Bacteroidetes spp. than males107. A study specifically analysing for a sex–diet interaction in diverse vertebrate species including fish, mice, and humans confirmed that diet has sex-specific effects on the gut microbiome in two species of fish, affects Fusobacteria spp. levels in humans, but does not seem to affect the microbiome in laboratory mice108. The lack of effect of diet on sex difference in the gut microbiome in laboratory mice may reflect the highly simplified diets they are fed and the artificial environment in which they are maintained109.Whether sex differences in the effects of diet on the gut microbiome in humans contributes to sex differences in diseases associated with dysbiosis, such as inflammatory bowel disease requires consideration. These data also imply that therapeutic approaches to treat diseases associated with dysbiosis may need to be different for males and females.

Effects of age and reproductive status

The age and reproductive status of an individual are also important determinants of sex-related differences in immune responses (Fig. 1). In the following section, we highlight some of the key immunological differences that are seen between the sexes at different stages of life.

In utero. Adverse fetal conditions may cause epigenetic adaptations leading to altered gene activity that can persist throughout life, including immunological programming110. Sex-differential developmental programming in utero results in sex differences in the local milieu and immune system development. Female fetuses have greater adaptability to intra-uterine stress than males. The placentas from premature (that is, born at <32 weeks gestation) male fetuses tend to be more chronically inflamed compared with those from female fetuses111, providing females survival benefits from better cardiovascular stability and lower levels of circulating cytokines. Human male testes produce androgens from 10 weeks of gestation112, leading to early development of androgen-dependent sex differences in immunity. Male neonates have higher cord blood IgE levels than females113, a fetal product that may predict the development of atopy.

Birth to 5 years of age. At birth the fetus transitions from the placenta to the outside environment and is bombarded with new antigens. Multiple studies have investigated neonatal immunity using cord blood samples due to the availability of large blood volumes, but few have specifically looked for sex differences. Cord blood mononuclear cell reactivity to TLR agonists in full term infants and pre-term infants that were born at <33 weeks of gestation is not affected by sex in either group114. However, human male infants have higher monocyte and basophil counts compared to females up until 13 months of age, at least in high pathogen burden settings115. NK cell frequencies are higher in male than female children25. Infant males have greater pro-inflammatory responses than females following stimulation with either LPS or mitogens116, all suggesting that males develop more robust innate immunity compared with females in early life.

Female cord blood contains higher numbers of CD4+ T cells, higher CD4/CD8 T cell ratios and lower numbers of CD8+ T cells and NK cells than cord blood from males, and these differences persist throughout childhood. By contrast, B cell numbers are comparable in male and female children25,26. The existence of these sex differences before puberty is often interpreted as evidence for genetic differences between the sexes. Neonatal castration experiments in rodents illustrate that the neonatal sex steroid milieu influences thymic development causing sex differences in the peripheral T cell compartment, including lower CD4/CD8 T cell ratios and higher NK T cell and CD4+CD25+FOXP3+ Treg cell numbers in neonatal males117. By contrast, there are no sex differences in human Treg cell frequencies in Australian infants from birth to one year of age118. Nigerian female children (aged 5–12 years) have lower IgA levels, but equivalent IgG and IgM levels, compared with males119.

Puberty. The multiple effects of sex steroids on immune cells play a prominent role in sex differences in inflammatory status during puberty. Although infant males may produce higher inflammatory responses than females, after puberty inflammatory responses are consistently higher in females than in males120. Females continue to have higher CD4+ T cell counts and higher CD4/CD8 T cell ratios than males throughout adulthood27,121, whereas males have higher numbers of Treg cells33. Gene expression studies in mice show that post-pubertal females show increased expression of genes associated with the adaptive immune response (for example, immunoglobulin and B cell receptor genes), whereas males show increased expression of genes that are associated with innate responses (for example, serum amyloid A, haptoglobin and plasminogen activator inhibitor 2 as well as Ccl9 and Ccr1)122.

Because sex steroids profoundly affect the immune response, it is not surprising that hormonal changes during the female menstrual cycle underlie cyclical changes in immune function and exacerbation of diseases, with pronounced fluctuations in immune cell numbers and function occurring over the menstrual cycle, including increased numbers of Treg cells when E2 concentrations are highest before ovulation123.

Reproductive senescence. Women, worldwide, have a longer lifespan than males, with biological factors, including changes in sex steroid concentrations and X chromosome diploidy, having a significant role124. With age, concentrations of sex steroids decline rapidly for females and more gradually for males, paralleling a progressive functional decline in the immune system of both sexes125. One of the most well characterized attributes of an ageing immune system is an aberrant chronic low-grade pro-inflammatory state, thought to occur to a greater extent in females than males35. NK cell numbers increase with age, with the kinetics of this rise being greater for females than males126. Female menopause is associated with a decline in certain lymphocyte subsets, but elderly males experience a more rapid decline in numbers of B cells and various CD4+ T cell subsets and show lower levels of T cell proliferation than females, along with a more modest increase in CD4+ memory T cells following antigen re-exposure34,126. A population of B cells referred to as 'age-associated B cells' has been linked with the development of autoimmune diseases in mice and humans, and these cells are found in higher frequencies in aged female mice than in aged male mice127.

Sex differences in the pathogenesis of diseases

Autoimmune diseases. Women represent 80% of all cases of autoimmunity in the US128. Sex differences in the incidence of autoimmunity are most pronounced for Sjögren syndrome, systemic lupus erythematosus, thyroid diseases (such as Hashimoto thyroiditis and Graves disease), scleroderma, and myasthenia gravis, with significantly more women afflicted than men (Fig. 2). Although less common, there are some autoimmune diseases, including myocarditis and idiopathic pulmonary fibrosis, that show greater incidence in males than females, which is hypothesized to reflect higher TH1 cell responses to self antigens during the acute phase of these autoimmune diseases129.

Figure 2: Sex bias in infectious diseases, inflammatory diseases and cancers.
figure2

At the extremes, males and females show robust differences in their susceptibility to autoimmunity and cancers. Generally, females show increased susceptibility to autoimmune disease development and males show increased susceptibility to non- reproductive malignant cancers. Although at a less pronounced magnitude, sex differences are also seen in susceptibility to various infectious diseases. Reproductive status, including pregnancy, as well as immune-mediated pathology contributes to female-biased infectious diseases, whereas pathogen-associated damage, including delayed clearance, is associated with male-biased infectious diseases. MERS, Middle East respiratory syndrome.

PowerPoint slide

Animal models, including the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and the nonobese diabetic (NOD) mouse model of spontaneous type 1 diabetes, have been used to characterize the immunological and hormonal causes of sex differences in autoimmune diseases. The incidence and severity of autoimmune disease in NOD mice and in EAE models is higher in female than in male mice. Castration of males increases, whereas ovariectomy of females decreases, the incidence of autoimmune diseases in mouse models130. In EAE mice and in PBMCs from patients with multiple sclerosis, females show greater activation of TH1 cells and increased levels of IFNγ production, whereas males exhibit greater TH17 cell responses owing to androgen receptor regulation of PPARα expression in T cells32. In female mice with EAE and women with severe forms of multiple sclerosis, administration of high doses of oestrogens suppress cell-mediated immune responses and relieves disease symptoms130,131. In men with multiple sclerosis, topical treatment with a gel containing testosterone slows brain atrophy and shifts peripheral immune responses by reducing the numbers of CD4+ T cells and PBMC production of IL-2 and increasing numbers of NK cells and PBMC production of TGFβ132 Thus, administration of hormone supplements to patients with autoimmune diseases may have novel therapeutic applications.

Malignancy. Sex is an important factor in the pathogenesis and prognosis of many cancers that occur outside of the reproductive tract (Fig. 2). For the majority of cancers throughout life, the risk of malignancy is higher for males133. Males have an almost twofold greater risk of mortality from all malignant cancers than do females134, with sex-differential outcomes being greatest for larynx, oesophagus, bladder and lung cancers134. This male-biased mortality is hypothesized to reflect differences in cancer aetiology134, including sex differences in viral infection, immune function, hormonal regulation, gene expression, sex chromosome complement, oxidative damage, autophagy, or a combination of factors134,135. Even treatments for cancers show sex-specific outcomes. Immune checkpoint inhibitors are revolutionizing cancer treatment, and some treatments, including programmed cell death 1 ligand 1 (PDL1)-specific monoclonal antibodies, appear to be more efficacious in female patients compared with male patients with melanoma136. The sex-differential effects of cancer chemotherapies with immunomodulatory properties and cancer vaccines require dedicated research.

Infectious diseases. The sexes differ in the severity, prevalence, and pathogenesis of infections caused by viruses, bacteria, parasites and fungi, with males generally more susceptible to these infections than females137 (Fig. 2). These differences are observed for infectious diseases acquired via multiple routes such as person-to-person, vector-borne, blood-borne, and food and water borne124, with sex differences in immunity playing a major role138. Newborn males are more vulnerable to infections and death than females139. In several developing countries, school-age male children have higher rates of protozoan infections (such as, malaria caused by Plasmodium falciparum, visceral leishmaniasis and Entameba histolytica induced amoebic liver abscess), trematode infections (such as, schistosomiasis caused by Schistosoma mansoni) and nematode infections (such as those with Necator americanus, Toxocara spp. and Wuchereria bancrofti)140. Among adults, untreated HIV-1-infected women have greater CD8+ T cell activation than men when adjusted for viral load and over 40% less circulating HIV RNA than men; however, when matched with men by HIV RNA load, woman have a 1.6-fold higher risk of developing AIDS141. Although exposure to influenza A viruses is often higher in men, fatality following exposure to pathogenic influenza A viruses is higher in women; by contrast, the prevalence of serum hepatitis B virus (HBV) surface antigen, HBV DNA titers and development of hepatocellular carcinoma is higher in men than women. In most countries, tuberculosis notification is twice as high for men than women. Clinical cryptococcosis is 10 times higher for immunocompromised men than women. Heightened immunity to pathogens among females contributes to lower intensity (that is viral load within an individual) and prevalence (that is number of infected individuals within a population) of many infections for females than males, but it may increase disease symptoms and severity among females compared with males137.

Vaccines. Sex differences have been described in immunity to multiple vaccines, including both inactivated vaccines (such as vaccines against brucellosis, diphtheria, hepatitis A, hepatitis B, herpes simplex virus-2 infection (genital herpes), influenza, meningococcal meningitis, pneumococcal disease (using pneumococcal polysaccharide), rabies and tetanus) and live vaccines (such as those against measles, rubella, smallpox, Venezuelan equine encephalitis, and yellow fever), in both children and adults142. The biological differences between the sexes is a major source of variation in the immune response to vaccination11,124 (Table 4). Antibody responses to bacterial and viral vaccines are often higher in females than males (Table 4). This could mean that the effective vaccine dose is lower for females than for males. For example, in dose response studies with the inactivated influenza vaccine, human females vaccinated with a half dose influenza vaccine achieved equivalent antibody titres to males vaccinated with full dose vaccine143. Females consistently report more frequent and severe local and systemic reactions to viral and bacterial vaccines than males, at least among young and ageing adults11,124,142, reflecting either a reporting bias or greater inflammatory responses among females than males11. Whether sex differences in immune responses to vaccines are caused by genetic, hormonal and environmental factors, or a combination, requires consideration.

Table 4 Sex differences in responses to vaccines in humans

Conclusions and perspective

The basis for personalized medicine is that unique aspects of our biology, including our immune responses, will define novel targets for more effective prevention and treatment of immune-related diseases. In this Review, we provide evidence that sex is one variable that influences innate and adaptive immune responses, resulting in sex-specific outcomes from infectious and autoimmune diseases, malignancies, and vaccines. If the long-term goal of personalizing treatments for immune-mediated diseases is effective treatment for all individuals, then will we ultimately treat males and females differently in an effort to protect them equally? Future studies must identify the precise factors mediating sex differences in the immune responses, knowing that this will probably reflect complex interactions among hormones, genes and our environment (both biotic and abiotic). Sex-based differences in the activity of the innate and adaptive immune responses likely have evolved through a process of convergent evolution, in which the fundamental mechanisms that underlie increased survival and reproductive success have sex-specific effects on immune function.

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Acknowledgements

The authors thank O. Hall and J. Peretz for assistance with tables, A. Pekosz and M. Plebanski for constructive comments on an earlier draft, and three anonymous reviewers who provided feedback that assisted with improving this Review.

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Correspondence to Sabra L. Klein.

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Klein, S., Flanagan, K. Sex differences in immune responses. Nat Rev Immunol 16, 626–638 (2016). https://doi.org/10.1038/nri.2016.90

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