madman
Super Moderator
SUMMARY
Immune responses to antigens, including innocuous, self, tumor, microbial, and vaccine antigens, differ between males and females. The quest to uncover the mechanisms for biological sex differences in the immune system has intensified, with considerable literature pointing toward sex hormonal influences on immune cell function. Sex steroids, including estrogens, androgens, and progestins, have profound effects on immune function. As such, drastic changes in sex steroid concentrations that occur with aging (e.g., after puberty or during the menopause transition) or pregnancy impact immune responses and the pathogenesis of immune-related diseases. The effect of sex steroids on immunity involves both the concentration of the ligand and the density and distribution of genomic and nongenomic receptors that serve as transcriptional regulators of immune cellular responses to affect autoimmunity, allergy, infectious diseases, cancers, and responses to vaccines. The next frontier will be harnessing these effects of sex steroids to improve therapeutic outcomes.
*ESTROGENS AND ESTROGEN RECEPTOR SIGNALING
*ER SIGNALING IN NEUTROPHILS
*ER SIGNALING IN NATURAL KILLER CELLS
*ER SIGNALING IN MACROPHAGES AND MONOCYTES
*ER SIGNALING IN DENDRITIC CELLS
*ER SIGNALING IN T CELLS
*ER SIGNALING IN B CELLS
*AR SIGNALING IN NEUTROPHILS
*AR SIGNALING IN NK CELLS
*AR SIGNALING IN MONOCYTES AND MACROPHAGES
*AR SIGNALING IN T CELLS
*AR SIGNALING IN B CELLS
*PROGESTERONE AND PR SIGNALING
*PR SIGNALING IN INNATE IMMUNE CELLS
*PR SIGNALING IN T CELLS
*PR SIGNALING IN B CELLS
DISCUSSION
Sex steroid signaling impacts both innate and adaptive immune-cell responses. To date, more studies have manipulated sex steroid ligands rather than receptors (Table 1). These studies clearly highlight the diverse effects of sex steroid concentrations on immune function. We identify the molecular and cellular mechanisms altered by the binding of E2, P4, and testosterone to their respective receptors in immune cells, which could provide evidence for targetable therapies.
As nuclear receptors, sex steroid receptors directly regulate immune responses at the transcriptional level to alter disease outcomes. Studies in cancer immunology have made the most progress in identifying the immunological pathways in innate and adaptive immune cells that are regulated by sex steroid receptor activation and have started to harness this for therapeutic treatments for reproductive cancers (e.g., breast and prostate cancers).223,224 Application of findings in cancer immunology, including observations of AR signaling suppression of CD8+ T cell function in the tumor microenvironment,157,159 to other diseases, such as autoimmunity, inflammation, and immunity to infectious disease, that have sex-specific and sex-differential outcomes is needed. There also is a need for greater consideration of PR signaling within diverse immune cell populations, including DCs, macrophages, and NK cells, especially given the known immunological changes associated with morbidity and mortality from infections during pregnancy.225–227
Identification and improved specificity of the tools available for manipulating sex steroid concentrations and receptor activity both in animal models and humans will allow for deeper interpretation into how sex steroid signaling alters immune cell function. One of the most well-utilized models to study the cause and effect of sex steroids on immune function is the removal of gonadal tissues (i.e., testes in males and ovaries in females) followed with exogenous replacement of the ligand (Table 1).
There are, however, additional methodologies for manipulating sex steroid receptor activity in immune cells using knockout technologies and pharmacological receptor agonists and antagonists (Table 2). Global knockout of sex steroid receptors has been used to evaluate function of receptor activity.68,69,164Sex steroid receptor activity in specific immune cell types can be analyzed with adoptive transfer of cells from a global receptor knockout mice into immune cell-depleted wild-type mice155 or with a cre-loxP-mediated recombination system to knock out sex steroid receptors in a specific immune cell population.228 For example, the select knockout of ERain CD4+ T cells67,72 or lysm expressing macrophages49 has yielded critical information about how ER signaling regulates the activity of these immune cells. The use of pharmacological sex steroid receptor agonists and antagonists(e.g., flutamide for AR, select ER modulators [SERMs] for ER, ormifepristone for PR159,197,229) has translational value for use in humans.
In preclinical and clinical settings, there can be bidirectional interactions between sex steroids and disease states, such that certain diseases can alter sex steroid concentrations and impact downstream signaling in immune cells. For example, hypogonadism (in both males and females) is a feature of several infectious diseases, including but not limited to HIV and tuberculosis, in humans.233,234 In adult mice infected with influenza A viruses, suppression of androgens in males and disruption of the estrous cycle in females is a consequence of acute disease.235,236 Detailed elsewhere are the diverse interactions between commensal microbes in the gastrointestinal tract and the synthesis and metabolism of sex steroids, which alters immunity and disease outcomes often differentially between the sexes.237,238 Commensal microorganisms can produce sex steroids, including androgens, to influence the immune landscape and disease outcomes.239 In addition to microbes having bidirectional interactions with sex steroids, hormone-based treatments for reproductive cancers can alter immune responses. Breast cancer patients receiving the ER antagonist tamoxifen or prostate cancer patients receiving androgen-deprivation therapy can have altered immune function.152,240 With these phenotypic differences in immunological outcomes, comes a recognition that sex steroid receptor signaling transcriptional regulates the activity in immune cells, which could have novel therapeutic potential.
Immune responses to antigens, including innocuous, self, tumor, microbial, and vaccine antigens, differ between males and females. The quest to uncover the mechanisms for biological sex differences in the immune system has intensified, with considerable literature pointing toward sex hormonal influences on immune cell function. Sex steroids, including estrogens, androgens, and progestins, have profound effects on immune function. As such, drastic changes in sex steroid concentrations that occur with aging (e.g., after puberty or during the menopause transition) or pregnancy impact immune responses and the pathogenesis of immune-related diseases. The effect of sex steroids on immunity involves both the concentration of the ligand and the density and distribution of genomic and nongenomic receptors that serve as transcriptional regulators of immune cellular responses to affect autoimmunity, allergy, infectious diseases, cancers, and responses to vaccines. The next frontier will be harnessing these effects of sex steroids to improve therapeutic outcomes.
*ESTROGENS AND ESTROGEN RECEPTOR SIGNALING
*ER SIGNALING IN NEUTROPHILS
*ER SIGNALING IN NATURAL KILLER CELLS
*ER SIGNALING IN MACROPHAGES AND MONOCYTES
*ER SIGNALING IN DENDRITIC CELLS
*ER SIGNALING IN T CELLS
*ER SIGNALING IN B CELLS
*AR SIGNALING IN NEUTROPHILS
*AR SIGNALING IN NK CELLS
*AR SIGNALING IN MONOCYTES AND MACROPHAGES
*AR SIGNALING IN T CELLS
*AR SIGNALING IN B CELLS
*PROGESTERONE AND PR SIGNALING
*PR SIGNALING IN INNATE IMMUNE CELLS
*PR SIGNALING IN T CELLS
*PR SIGNALING IN B CELLS
DISCUSSION
Sex steroid signaling impacts both innate and adaptive immune-cell responses. To date, more studies have manipulated sex steroid ligands rather than receptors (Table 1). These studies clearly highlight the diverse effects of sex steroid concentrations on immune function. We identify the molecular and cellular mechanisms altered by the binding of E2, P4, and testosterone to their respective receptors in immune cells, which could provide evidence for targetable therapies.
As nuclear receptors, sex steroid receptors directly regulate immune responses at the transcriptional level to alter disease outcomes. Studies in cancer immunology have made the most progress in identifying the immunological pathways in innate and adaptive immune cells that are regulated by sex steroid receptor activation and have started to harness this for therapeutic treatments for reproductive cancers (e.g., breast and prostate cancers).223,224 Application of findings in cancer immunology, including observations of AR signaling suppression of CD8+ T cell function in the tumor microenvironment,157,159 to other diseases, such as autoimmunity, inflammation, and immunity to infectious disease, that have sex-specific and sex-differential outcomes is needed. There also is a need for greater consideration of PR signaling within diverse immune cell populations, including DCs, macrophages, and NK cells, especially given the known immunological changes associated with morbidity and mortality from infections during pregnancy.225–227
Identification and improved specificity of the tools available for manipulating sex steroid concentrations and receptor activity both in animal models and humans will allow for deeper interpretation into how sex steroid signaling alters immune cell function. One of the most well-utilized models to study the cause and effect of sex steroids on immune function is the removal of gonadal tissues (i.e., testes in males and ovaries in females) followed with exogenous replacement of the ligand (Table 1).
There are, however, additional methodologies for manipulating sex steroid receptor activity in immune cells using knockout technologies and pharmacological receptor agonists and antagonists (Table 2). Global knockout of sex steroid receptors has been used to evaluate function of receptor activity.68,69,164Sex steroid receptor activity in specific immune cell types can be analyzed with adoptive transfer of cells from a global receptor knockout mice into immune cell-depleted wild-type mice155 or with a cre-loxP-mediated recombination system to knock out sex steroid receptors in a specific immune cell population.228 For example, the select knockout of ERain CD4+ T cells67,72 or lysm expressing macrophages49 has yielded critical information about how ER signaling regulates the activity of these immune cells. The use of pharmacological sex steroid receptor agonists and antagonists(e.g., flutamide for AR, select ER modulators [SERMs] for ER, ormifepristone for PR159,197,229) has translational value for use in humans.
In preclinical and clinical settings, there can be bidirectional interactions between sex steroids and disease states, such that certain diseases can alter sex steroid concentrations and impact downstream signaling in immune cells. For example, hypogonadism (in both males and females) is a feature of several infectious diseases, including but not limited to HIV and tuberculosis, in humans.233,234 In adult mice infected with influenza A viruses, suppression of androgens in males and disruption of the estrous cycle in females is a consequence of acute disease.235,236 Detailed elsewhere are the diverse interactions between commensal microbes in the gastrointestinal tract and the synthesis and metabolism of sex steroids, which alters immunity and disease outcomes often differentially between the sexes.237,238 Commensal microorganisms can produce sex steroids, including androgens, to influence the immune landscape and disease outcomes.239 In addition to microbes having bidirectional interactions with sex steroids, hormone-based treatments for reproductive cancers can alter immune responses. Breast cancer patients receiving the ER antagonist tamoxifen or prostate cancer patients receiving androgen-deprivation therapy can have altered immune function.152,240 With these phenotypic differences in immunological outcomes, comes a recognition that sex steroid receptor signaling transcriptional regulates the activity in immune cells, which could have novel therapeutic potential.
