Abstract
The study investigated influence of sex and age on splenic myeloid dendritic cells (DCs) from Dark Agouti rats. Freshly isolated DCs from young males exhibited less mature phenotype and greater endocytic capacity compared with those from age-matched females. Upon LPS stimulation in vitro they were less potent in stimulating allogeneic CD4+ cells in mixed leukocyte reaction (MLR), due to lower expression of MHC II, and greater NO and IL-10 production. In accordance with higher TGF-β production, young male rat DCs were less potent in stimulating IL-17 production in MLR than those from young females. Irrespective of sex, endocytic capacity and responsiveness of DCs to LPS stimulation in culture, judging by their allostimulatory capacity in MLR decreased with age, reflecting decline in MHC II surface density followed by their greater NO production; the effects more prominent in females. Additionally, compared with LPS-stimulated DCs from young rats, those from sex-matched aged rats were more potent in stimulating IL-10 production in MLR, whereas capacity of DCs from aged female and male rats to stimulate IL-17 production remained unaltered and decreased, respectively. This reflected age-related shift in IL-6/TGF-β production level ratio in LPS-stimulated DC cultures towards TGF-β, and sex-specific age-related remodeling CD4+ cell cytokine pathways. Additionally, compared with LPS-stimulated DCs from young rats, those cells from sex-matched aged rats were less potent in stimulating IFN-γ production in MLR, the effect particularly prominent in MLRs encompassing male rat DCs. The study showed that stimulatory and polarizing capacity of DCs depends on rat sex and age.
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10522_2019_9845_MOESM1_ESM.tif
Supplementary material 1 (TIFF 1995 kb). Online Resource 1 Overnight culturing of splenic DCs from young and aged rats of both sexes in medium alone induced their spontaneous activation. Scatter plots indicate frequency of b CD80+; c CD86+ and d CD40+ cells within CD103+ DCs and mean fluorescence intensity (MFI) for a MHC II; b CD80; c CD86; d CD40 on corresponding marker positive CD103+ DCs freshly isolated (Fresh) or left unstimulated (−LPS) overnight from young and aged Dark Agouti (DA) rats of both sexes (see Materials and methods section). Two way ANOVA showed significant interaction between the effects of sex and age for frequency of CD40+ (F(1,20) = 34.21; p<0.001) cells among CD103+ DCs in −LPS cultures and MFI for MHC II (F(1,20) = 34.68; p<0.001) and CD86 (F(1,20) = 14.7; p<0.01) on marker+ CD103+ DCs in −LPS cultures. Results are from one of two experiments with similar results (n = 6 animals/group). The data are shown as mean ± SEM. Horizontal lines within scatter plots indicate median values. * p<0.05; ** p<0.01; *** p<0.001; ## p<0.01; ### p<0.001; # vs female; $$$ p<0.001; $ vs Fresh
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Supplementary material 2 (TIFF 742 kb). Online Resource 2 Proliferation of allogeneic CD4+ T cells co-cultured with DCs in MLR exhibited cell ratio dependent changes irrespective of age and sex of DCs donor. Scatter plots indicate frequency of allogeneic CD4+ T cells with diminished CFSE intensity (gated as shown in Fig. 5) stimulated in MLR with splenic DCs left unstimulated (−LPS) or stimulated with LPS (+LPS) at 1:10, 1:20 and 1:40 ratios, from young and aged Dark Agouti (DA) rats of both sexes. Two way ANOVA showed significant interaction between the effects of sex and age for frequency of cells with diminished CFSE at 1:10 DC:T cell ratio (F(1,20) = 69.11; p<0.001) in −LPS and (F(1,20) = 21.30; p<0.001) in +LPS cultures. Results are from one of two experiments with similar results (n = 6 animals/group). The data are shown as mean ± SEM. Horizontal lines within scatter plots indicate median values. ** p<0.01; *** p<0.001; # p<0.05; ### p<0.001; # vs female; $$$ p<0.001; $ vs −LPS
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Stojić-Vukanić, Z., Pilipović, I., Bufan, B. et al. Age and sex determine CD4+ T cell stimulatory and polarizing capacity of rat splenic dendritic cells. Biogerontology 21, 83–107 (2020). https://doi.org/10.1007/s10522-019-09845-y
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DOI: https://doi.org/10.1007/s10522-019-09845-y