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. 2022 Nov 1;11(11):bio059334.
doi: 10.1242/bio.059334. Epub 2022 Nov 9.

Postnatal depletion of maternal cells biases T lymphocytes and natural killer cells' profiles toward early activation in the spleen

Flore S Castellan  1 , Naoki Irie  1
Affiliations

Postnatal depletion of maternal cells biases T lymphocytes and natural killer cells' profiles toward early activation in the spleen

Flore S Castellan et al. Biol Open. .

Abstract

The maternal cells transferred into the fetus during gestation persist long after birth in the progeny. These maternal cells have been hypothesized to promote the maturation of the fetal immune system in utero but there are still significant gaps in our knowledge of their potential roles after birth. To provide insights into these maternal cells' postnatal functional roles, we set up a transgenic mouse model to specifically eliminate maternal cells in the neonates by diphtheria toxin injection and confirmed significant depletion in the spleens. We then performed immunophenotyping of the spleens of two-week-old pups by mass cytometry to pinpoint the immune profile differences driven by the depletion of maternal cells in early postnatal life. We observed a heightened expression of markers related to activation and maturation in some natural killer and T cell populations. We hypothesize these results to indicate a potential postnatal regulation of lymphocytic responses by maternal cells. Together, our findings highlight an immunological influence of maternal microchimeric cells postnatally, possibly protecting against adverse hypersensitivity reactions of the neonate at a crucial time of new encounters with self and environmental antigens.

Keywords: Maternal Cells; Microchimerism; Neonatal Immunity.

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Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Mouse breeding charts. (A) Mouse crossings to obtain the F2 pups in which DTR(+/-)MHC(b/d) maternal cells numbers were estimated by FACS/qPCR. (B) Mouse crossings to obtain the F1 and control pups whose spleens were immunophenotyped by mass cytometry. B6 and Balb/C refer to the C57BL/6JJcl and BALB/cByJJcl background strains, and B6CF1 and (B6CF1)B6 refer to hybrid backgrounds from crossing these strains. The major histocompatibility complex (MHC) alleles of each mouse are indicated in parenthesis. DTR: diphtheria toxin receptor. MMc: maternal microchimerism. Created with BioRender.com.
Fig. 2.
Fig. 2.
Maternal cells’ detection pipeline. Pipeline combining FACS sorting and TaqMan duplex qPCR for detection and estimation of maternal cells ratios R in the pups’ spleen and thymus. DTR: diphtheria toxin receptor. MHC: major histocompatibility complex. MMc: maternal microchimerism. Created with Servier Medical Art.
Fig. 3.
Fig. 3.
Detection and depletion of maternal cells in the spleens and thymus of mouse pups. (A) Numbers of F2 pups with the indicated number of organs positive for maternal cells out of the spleen and the thymus assayed by the FACS-qPCR pipeline following PBS or diphtheria toxin (DT) injections, n=10 mice for each group. (B) Estimated number of maternal cells per 107 host cells in the spleens and thymus of F2 pups injected with DT (n=10 mice) or PBS (n=10 mice). The distribution of the data is represented with boxplots. Dots represent individual sample points. Brunner–Menzel's test: P=0.012.
Fig. 4.
Fig. 4.
Visual representation of the cell clustering performed by unsupervised meta clustering and manual merging. (A) Heatmap representing the median of 0-1 transformed marker expression of the 16 markers across the initial 20 cell populations obtained with FlowSOM. The dendrogram on the left represents the hierarchical similarity between the 20 meta clusters (metric: Euclidean distance; linkage: average). The 14 merged clusters are identified by the color bar on the left of the heatmap. The 20 initial clusters are identified by their number at the right of the heatmap, with the relative proportion of each cluster over the total cell population indicated in brackets. The total cell population represents 141,174 cells per sample with n=10 mice. (B) UMAP plot based on the expression of the 16 immune cell markers. From each of the 10 mouse spleen samples, 2000 cells were randomly selected. Cells are colored according to the manual merging of the 20 cell populations obtained with FlowSOM into 14 populations.
Fig. 5.
Fig. 5.
Proportions of the immune cell populations and differential analysis of marker expression in these populations between splenic cells from reference pups (control, n=5) and pups depleted of maternal cells (MMc-depleted, n=5). (A) Relative abundance of the 14 manually identified cell populations in each sample of the dataset, represented with a barplot, over the 141,174 subsampled cells per sample. (B) Heatmap of the normalized expression of the functional markers in the cell populations that are significantly differentially expressed between control and MMc-depleted conditions. Each median marker expression was normalized to have a mean of 0 and a standard deviation of 1. In parenthesis, value g indicates Hedges’ g measure of the effect size and the value P corresponds to the P-value for rejecting the general linear hypothesis of a null regression coefficient for the population marker expression corresponding to the condition.
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