The Molecular Signature Underlying the Thymic Migration and Maturation of TCRαβ+CD4+CD8- Thymocytes

Teng, Fei; Zhou, Yu-Bin; Jin, Rong; Chen, Yu; Pei, Xiao-Yan; Liu, Yuanfeng; Dong, Jie; Wang, Wei; Pang, Xuewen; Qian, Xiaoping; Chen, Weifeng; Zhang, Yu; Ge, Qing

doi:10.1371/journal.pone.0025567

Cited by 23 publications

(26 citation statements)

References 75 publications

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“…CCchemokine receptor 7 (CCR7) is an important receptor for the medullary positioning of SP cells and an indispensable signal mediator for unperturbed thymic T-cell differentiation and maturation (24,25). CCR7 remains at low levels in newly generated SP cells and is quickly upregulated and maintained at high levels afterwards (26). CD8 ϩ CCR7 Ϫ T cells are more sensitive to spontaneous apoptosis than CD8 ϩ CCR7 ϩ T cells (27).…”

Section: Conditional Inactivation Of Fbw7 In the T-cell Lineages Impementioning

confidence: 99%

Fbw7 Targets GATA3 through Cyclin-Dependent Kinase 2-Dependent Proteolysis and Contributes to Regulation of T-Cell Development

Kitagawa

Shibata

Matsumoto

et al. 2014

Molecular and Cellular Biology

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cProper development of T cells depends on lineage-specific regulators controlled transcriptionally and posttranslationally to ensure precise levels at appropriate times. Conditional inactivation of F-box protein Fbw7 in mouse T-cell development resulted in reduced thymic CD4 single-positive (SP) and splenic CD4؉ and CD8 ؉ cell proportions. Fbw7 deficiency skewed CD8 SP lineage differentiation, which exhibited a higher incidence of apoptosis. Similar perturbations during development of CD8-positive cells were reported with transgenic mice, which enforced GATA3 (T-cell differentiation regulator) expression throughout T-cell development. We observed augmented GATA3 in CD4/CD8 double negative (DN) stage 4, CD4 SP, and CD8 SP lineages in Fbw7-deficient thymocytes. Using overexpressed proteins in cultured cells, we demonstrated that Fbw7 bound to, ubiquitylated, and destabilized GATA3. Two Cdc4 phosphodegron (CPD) candidate sequences, consensus Fbw7 recognition domains, were identified in GATA3, and phosphorylation of Thr-156 in CPD was required for Fbw7-mediated ubiquitylation and degradation. Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. These observations suggest that Fbw7-mediated GATA3 regulation with CDK2-mediated phosphorylation of CPD contributes to the precise differentiation of T-cell lineages.

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Section: Conditional Inactivation Of Fbw7 In the T-cell Lineages Impementioning

confidence: 99%

Fbw7 Targets GATA3 through Cyclin-Dependent Kinase 2-Dependent Proteolysis and Contributes to Regulation of T-Cell Development

Kitagawa

Shibata

Matsumoto

et al. 2014

Molecular and Cellular Biology

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“…Comparative gene expression analysis of these four subsets revealed that thymocytes at the SP4 stage are the most mature ones and acquire the thymus egress capability by expressing the highest levels of S1P 1 and CD62L [28]. An adoptive transfer of various SP subsets directly into the thymus also supported SP4 cells as the main population that leave the thymus and enter the periphery [4].…”

Section: Introductionmentioning

confidence: 96%

Homeostatic Properties and Phenotypic Maturation of Murine CD4+ Pre-Thymic Emigrants in the Thymus

Dong

Chen

et al. 2013

PLoS ONE

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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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“…Whereas CD62L is important for the homing of mature T-lymphocytes to secondary lymphoid organs21, S1P expressed by neural crest-derived pericytes on the vessel wall bind S1P 1 on mature thymocytes and thereby promote their egress at the corticomedullary junction22232425. Qa2 is a non-classical MHC class I molecule used as a marker for thymocyte maturation and expression of Qa2 is up-regulated in the final SP4 stage of thymocyte development just before their exit to the periphery2627.…”

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confidence: 99%

Thymic exosomes promote the final maturation of thymocytes

Lundberg

Berglund

Skogberg

et al. 2016

Sci Rep

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Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4+CD25− cells into mature thymocytes with S1P1+Qa2+ and CCR7+Qa2+ phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4+CD25+FoxP3+ thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC’s is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus.

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The Molecular Signature Underlying the Thymic Migration and Maturation of TCRαβ+CD4+CD8- Thymocytes

Cited by 23 publications

References 75 publications

Fbw7 Targets GATA3 through Cyclin-Dependent Kinase 2-Dependent Proteolysis and Contributes to Regulation of T-Cell Development

Fbw7 Targets GATA3 through Cyclin-Dependent Kinase 2-Dependent Proteolysis and Contributes to Regulation of T-Cell Development

Homeostatic Properties and Phenotypic Maturation of Murine CD4+ Pre-Thymic Emigrants in the Thymus

Thymic exosomes promote the final maturation of thymocytes

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