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Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus.

Dong J, Chen Y, Xu X, Jin R, Teng F, Yan F, Tang H, Li P, Sun X, Li Y, Wu H, Zhang Y, Ge Q - PLoS ONE (2013)

Bottom Line: Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+) pre-RTEs in thymic perivascular space.Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs.The dendritic cell-driven Qa2 induction of CD4(+) pre-RTEs is independent of MHC class II and Aire molecules.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, Peking University Health Science Center, Beijing, China.

ABSTRACT
After a tightly regulated developmental program in the thymus, "mature" single positive (SP) thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs) are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4(+) pre-RTEs, a population of CD4(+) SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4(+) pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs' better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+) pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4(+) pre-RTEs is independent of MHC class II and Aire molecules.

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Pre-RTEs consist of SP4 thymocytes in adult mice but a mixture of SP3 and SP4 thymocytes in neonatal and young mice.A. FITC intrathymic injection of C57BL/6 mice were used to analyze the phenotype of RTEs (FITC+ cells) at 2, 4, and 6 weeks of age. B. RAG2p-GFP mice were also used to study RTEs (GFPhi cells). The numbers in the plot represent the mean and standard deviation of the ratios of Qa2+CD69- cells in FITC+ or GFPhi CD4+CD8- T cells in the lymph nodes (LN) and spleen. Three to five mice were analyzed.
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pone-0056378-g001: Pre-RTEs consist of SP4 thymocytes in adult mice but a mixture of SP3 and SP4 thymocytes in neonatal and young mice.A. FITC intrathymic injection of C57BL/6 mice were used to analyze the phenotype of RTEs (FITC+ cells) at 2, 4, and 6 weeks of age. B. RAG2p-GFP mice were also used to study RTEs (GFPhi cells). The numbers in the plot represent the mean and standard deviation of the ratios of Qa2+CD69- cells in FITC+ or GFPhi CD4+CD8- T cells in the lymph nodes (LN) and spleen. Three to five mice were analyzed.

Mentions: CD4+ SP thymocytes with SP4 phenotype have been shown to express the highest levels of S1P1 and CD62L compared to other SP subsets. It is thus expected that SP4 thymocytes are pre-RTEs in the thymus that have acquired egress capability. However, whether these cells compose the majority of pre-RTEs have not been directly proved. Two approaches were used to examine the phenotype of emigrants that have just left the thymus. First, FITC was introduced into the mice via intrathymic injection and the phenotype of FITC+CD4+ T cells in the lymph nodes and the spleen were analyzed 24 hours later (Fig. 1A). Second, RAG2p-GFP mice were sacrificed and the phenotype of GFPhiCD4+ T cells in the periphery was examined (Fig. 1B). Boursalian et al. have shown that GFPhi T cells in the periphery are RTEs that have left the thymus within a week [17]. Both methods gave very similar results that in mice with 6 weeks of age or older, more than 70% of RTEs were Qa2+, suggesting that the majority of pre-RTEs are SP4 thymocytes. In mice within 2 weeks of age, however, more than 70% of RTEs were Qa2-CD69-, indicating that thymocytes at the immature SP3 stage acquire egress capability and compose the main population of pre-RTEs during this period (Fig. 1A and 1B). As the appearance of SP4 cells in the thymus was not found until mice reaching 1 week of age [4], the rushing of cells with the SP3 phenotype out to the periphery at the neonatal stage may be important in establishing the peripheral T cell pool [29]. Alternatively, the SP3 thymocytes in neonatal and young mice may be different from the SP3s in adult mice. To exclude this possibility and to focus on pre-RTEs in adult animals, we used SP4 thymocytes purified from 6–8-week-old mice as pre-RTEs in the studies shown below.


Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus.

Dong J, Chen Y, Xu X, Jin R, Teng F, Yan F, Tang H, Li P, Sun X, Li Y, Wu H, Zhang Y, Ge Q - PLoS ONE (2013)

Pre-RTEs consist of SP4 thymocytes in adult mice but a mixture of SP3 and SP4 thymocytes in neonatal and young mice.A. FITC intrathymic injection of C57BL/6 mice were used to analyze the phenotype of RTEs (FITC+ cells) at 2, 4, and 6 weeks of age. B. RAG2p-GFP mice were also used to study RTEs (GFPhi cells). The numbers in the plot represent the mean and standard deviation of the ratios of Qa2+CD69- cells in FITC+ or GFPhi CD4+CD8- T cells in the lymph nodes (LN) and spleen. Three to five mice were analyzed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569422&req=5

pone-0056378-g001: Pre-RTEs consist of SP4 thymocytes in adult mice but a mixture of SP3 and SP4 thymocytes in neonatal and young mice.A. FITC intrathymic injection of C57BL/6 mice were used to analyze the phenotype of RTEs (FITC+ cells) at 2, 4, and 6 weeks of age. B. RAG2p-GFP mice were also used to study RTEs (GFPhi cells). The numbers in the plot represent the mean and standard deviation of the ratios of Qa2+CD69- cells in FITC+ or GFPhi CD4+CD8- T cells in the lymph nodes (LN) and spleen. Three to five mice were analyzed.
Mentions: CD4+ SP thymocytes with SP4 phenotype have been shown to express the highest levels of S1P1 and CD62L compared to other SP subsets. It is thus expected that SP4 thymocytes are pre-RTEs in the thymus that have acquired egress capability. However, whether these cells compose the majority of pre-RTEs have not been directly proved. Two approaches were used to examine the phenotype of emigrants that have just left the thymus. First, FITC was introduced into the mice via intrathymic injection and the phenotype of FITC+CD4+ T cells in the lymph nodes and the spleen were analyzed 24 hours later (Fig. 1A). Second, RAG2p-GFP mice were sacrificed and the phenotype of GFPhiCD4+ T cells in the periphery was examined (Fig. 1B). Boursalian et al. have shown that GFPhi T cells in the periphery are RTEs that have left the thymus within a week [17]. Both methods gave very similar results that in mice with 6 weeks of age or older, more than 70% of RTEs were Qa2+, suggesting that the majority of pre-RTEs are SP4 thymocytes. In mice within 2 weeks of age, however, more than 70% of RTEs were Qa2-CD69-, indicating that thymocytes at the immature SP3 stage acquire egress capability and compose the main population of pre-RTEs during this period (Fig. 1A and 1B). As the appearance of SP4 cells in the thymus was not found until mice reaching 1 week of age [4], the rushing of cells with the SP3 phenotype out to the periphery at the neonatal stage may be important in establishing the peripheral T cell pool [29]. Alternatively, the SP3 thymocytes in neonatal and young mice may be different from the SP3s in adult mice. To exclude this possibility and to focus on pre-RTEs in adult animals, we used SP4 thymocytes purified from 6–8-week-old mice as pre-RTEs in the studies shown below.

Bottom Line: Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+) pre-RTEs in thymic perivascular space.Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs.The dendritic cell-driven Qa2 induction of CD4(+) pre-RTEs is independent of MHC class II and Aire molecules.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, Peking University Health Science Center, Beijing, China.

ABSTRACT
After a tightly regulated developmental program in the thymus, "mature" single positive (SP) thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs) are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4(+) pre-RTEs, a population of CD4(+) SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4(+) pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs' better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+) pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4(+) pre-RTEs is independent of MHC class II and Aire molecules.

Show MeSH
Related in: MedlinePlus