XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner
Abstract Background Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immu...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Biology of Sex Differences |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13293-024-00597-0 |
| _version_ | 1797259545630736384 |
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| author | Carly J. Amato-Menker Quinn Hopen Andrea Pettit Jasleen Gandhi Gangqing Hu Rosana Schafer Jennifer Franko |
| author_facet | Carly J. Amato-Menker Quinn Hopen Andrea Pettit Jasleen Gandhi Gangqing Hu Rosana Schafer Jennifer Franko |
| author_sort | Carly J. Amato-Menker |
| collection | DOAJ |
| description | Abstract Background Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiota on humoral immune activation. Methods Male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed, and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotype. The functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, was evaluated ex vivo using mitogen stimulation of B cells. Additional influences of the gut microbiome on sex chromosome-dependent B cell activation was also evaluated by antibiotically depleting gut microbiota prior to HKSP immunization. Reconstitution of the depleted microbiome with short-chain fatty acid (SCFA)-producing bacteria tested the impact of SCFAs on XX-dependent immune activation. Results XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria enhanced fecal SCFA concentrations and increased humoral responses in XX, but not XY, FCG mice. However, exposure to the SCFA propionate alone did not enhance mitogenic B cell stimulation in ex vivo studies. Conclusions FCG mice have been used to assess sex hormone and sex chromosome complement influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphism. |
| first_indexed | 2024-04-24T23:11:08Z |
| format | Article |
| id | doaj.art-0e1c5481102a4ec4a029b27668a4000d |
| institution | Directory Open Access Journal |
| issn | 2042-6410 |
| language | English |
| last_indexed | 2024-04-24T23:11:08Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology of Sex Differences |
| spelling | doaj.art-0e1c5481102a4ec4a029b27668a4000d2024-03-17T12:12:00ZengBMCBiology of Sex Differences2042-64102024-03-0115112410.1186/s13293-024-00597-0XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent mannerCarly J. Amato-Menker0Quinn Hopen1Andrea Pettit2Jasleen Gandhi3Gangqing Hu4Rosana Schafer5Jennifer Franko6Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University School of MedicineAbstract Background Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiota on humoral immune activation. Methods Male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed, and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotype. The functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, was evaluated ex vivo using mitogen stimulation of B cells. Additional influences of the gut microbiome on sex chromosome-dependent B cell activation was also evaluated by antibiotically depleting gut microbiota prior to HKSP immunization. Reconstitution of the depleted microbiome with short-chain fatty acid (SCFA)-producing bacteria tested the impact of SCFAs on XX-dependent immune activation. Results XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria enhanced fecal SCFA concentrations and increased humoral responses in XX, but not XY, FCG mice. However, exposure to the SCFA propionate alone did not enhance mitogenic B cell stimulation in ex vivo studies. Conclusions FCG mice have been used to assess sex hormone and sex chromosome complement influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphism.https://doi.org/10.1186/s13293-024-00597-0X chromosomeFour Core GenotypeHKSPGut microbiomeKdm6aSCFA |
| spellingShingle | Carly J. Amato-Menker Quinn Hopen Andrea Pettit Jasleen Gandhi Gangqing Hu Rosana Schafer Jennifer Franko XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner Biology of Sex Differences X chromosome Four Core Genotype HKSP Gut microbiome Kdm6a SCFA |
| title | XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner |
| title_full | XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner |
| title_fullStr | XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner |
| title_full_unstemmed | XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner |
| title_short | XX sex chromosome complement modulates immune responses to heat-killed Streptococcus pneumoniae immunization in a microbiome-dependent manner |
| title_sort | xx sex chromosome complement modulates immune responses to heat killed streptococcus pneumoniae immunization in a microbiome dependent manner |
| topic | X chromosome Four Core Genotype HKSP Gut microbiome Kdm6a SCFA |
| url | https://doi.org/10.1186/s13293-024-00597-0 |
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