Oestrogen influences class switched B cell frequency exclusively in individuals with an XX sex chromosome complement
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB82324 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13935200_1.fastq.gz | Fastqsanger.gz | |||
| ERR13935200_2.fastq.gz | Fastqsanger.gz | |||
| ERR13935201_1.fastq.gz | Fastqsanger.gz | |||
| ERR13935201_2.fastq.gz | Fastqsanger.gz | |||
| ERR13935202_1.fastq.gz | Fastqsanger.gz |
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Project description: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 microbiome bacteria on humoral immune activation. Sham-operated and gonadectomized 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 phenotypes. Ex vivo studies investigated the functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, in mitogenic B cell activation. We further evaluated whether gut microbiome communities, or their metabolites, differentially influence immune cell activation in a sex chromosome-dependent manner. Endogenous gut microbiomes were antibiotically depleted and reconstituted with select short-chain fatty acid (SCFA)-producing bacteria prior to HKSP immunization and immune responses assessed. 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 increased humoral responses in XX, but not XY, FCG mice. This XX-dependent enhancement appears to be independent of SCFA production in males, while female XX-dependent responses relied on SCFAs. FCG mice have been used to assess sex hormones and sex chromosome complements 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 dimorphisms.
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Project description:We report that a large percentage of thymic B cells undergo class switching intrathymically. Thymic B cell class switching requires cognate T-B interaction. To determine whether B cell specificity was also important for thymic B cell class-switching, we sorted class-switched thymic B cells (CD19+B220+IgM-IgD-), unswitched B cells (CD19+B220+IgM+IgD+) and bulk splenic B cells in 3H9 heavy chain-fixed mice and performed high throughput sequencing analysis of the light chain of these populations. Results of this analysis indicated that class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells and splenic B cells. Further reactivity tests indicated that a large part of BCRs enriched in class-switched thymic B cells are autoreactive. These data suggest that autoreactive B cells are selected into class-switched population and expanded in the thymus. Light chain repertoire profiles of class-switched thymic B cells, unswithced thymic B cells and splenic B cells from 3H9 mice were generated by deep sequencing.
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