Abstract
The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF-β and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature CD4+CD8−/CD4−CD8+ single positive (SP) TCRαβhigh thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPARγ and STAT3, a transcription factor regulating the expression of PPARγ downstream genes, in male than in female rats. In aged thymi of both sexes the early CD4−CD8− double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature CD45RC+CD2− cells followed by decreased frequency of their DN and CD4+CD8+ double positive (DP) TCRαβ− descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) MFI on DP TCRαβint thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards CD4−CD8+ SP TCRαβhigh cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.
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This study was funded by the Ministry of Education, Science and Technological Development of Republic of Serbia (Grant Number 175050).
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Supplementary Fig. 1 Gating strategies for flow cytometry analyses of thymocytes. Flow cytometry dot plots represent (a) gating strategy for delineating CD4−CD8− double negative (R1), CD4+CD8+ double positive (R2), CD4+CD8− (R3) and CD4−CD8+ (R4) single positive thymocytes, (b) FMO control without anti-TCRαβ mAb and fully stained thymocytes (gated as shown above) for setting cut off boundaries for analysis of TCRαβ expression on CD4/CD8/TCRαβ stained thymocytes and (c) FMO control without annexin V and fully stained thymocytes for setting cut off boundaries for analysis of annexin V expression on CD4/CD8/ TCRαβ/annexin V stained thymocytes (TIFF 969 kb)
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Supplementary Fig. 2 Sex differences in age-related alterations of the frequency of SP CD4+CD8− and CD4−CD8+ TCRαβ− and TCRαβint thymocytes. Representative flow cytometry dot plots show TCRαβ staining of (a) CD4+CD8− and (b) CD4−CD8+ single positive (SP) thymocytes of young and old female and male Dark Agouti (DA) rats (gating strategy is displayed in Suppl. Figure 1). Scatter plots indicate the frequency of (a) CD4+CD8− and (b) CD4−CD8+ (left) SP TCRαβ− (R1) and (right) TCRαβint (R2) thymocytes of young and old female and male DA rats. Two way ANOVA showed significant interaction between the effects of sex and age for frequency of CD4−CD8+ (F(1,16) = 16.33, p < 0.001) SP TCRαβ− thymocytes. Data points, means and ± SD are from one of two experiments with similar results (n = 5). *p < 0.05; **p < 0.01; ***p < 0.001. FY, female young; MY, male young; FO, female old; MO, male old (TIFF 2548 kb)
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Nacka-Aleksić, M., Pilipović, I., Kotur-Stevuljević, J. et al. Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation. Biogerontology 20, 545–569 (2019). https://doi.org/10.1007/s10522-019-09816-3
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DOI: https://doi.org/10.1007/s10522-019-09816-3