Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery

Paiva, Ricardo; Lino, Andreia C.; Bergman, Marie‐Louise; Caramalho, Íris; Sousa, Ana E.; Zelenay, Santiago; Demengeot, Jocelyne

doi:10.1073/pnas.1221955110

Cited by 73 publications

(70 citation statements)

References 42 publications

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“…5C). To further establish whether the output of new tTreg cells from the thymus contributes to Treg cell expansion after UVB exposure, the expression of CD24/heat-stable Ag (24,25), a marker of recent thymic emigrants, was investigated. Notably, CD24 + Foxp3 + Treg cells were significantly increased in DLN, not in spleen, after UVB exposure (Fig.…”

Section: The Journal Of Immunologymentioning

confidence: 99%

Homeostasis of Thymus-Derived Foxp3+ Regulatory T Cells Is Controlled by Ultraviolet B Exposure in the Skin

Yamazaki

Nishioka

Kasuya

et al. 2014

The Journal of Immunology

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Accumulating evidence shows that immunological tolerance induced by Ag administration together with UVB irradiation is dependent on Foxp3+ CD4+ regulatory T (Treg) cells. However, the mechanisms by which UVB controls Treg cells in the skin are currently unclear. In this study, we have shown that exposure to UVB induced expansion of Treg cells up to 50–60% of the CD4+ T cells in the irradiated skin. The Treg cell expansion in the skin lasted for 2 wk after exposure, which contributed to homeostasis of Treg cells in the periphery later. UVB-expanded Treg cells formed clusters with dendritic cells and proliferated in situ. Furthermore, the expanded Treg cells appeared to derive from neuropilin 1+ thymus-derived Treg (tTreg) cells in the periphery because UVB-expanded Treg cells possessed Treg cell–specific CpG hypomethylation pattern, as seen in tTreg cells. These results collectively indicate that homeostasis of tTreg cells is controlled by UVB exposure in the skin. UVB therapy may be useful for not only inflammatory skin disorders, but also autoimmunity, transplantation, and allergy.

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Section: The Journal Of Immunologymentioning

confidence: 99%

Homeostasis of Thymus-Derived Foxp3+ Regulatory T Cells Is Controlled by Ultraviolet B Exposure in the Skin

Yamazaki

Nishioka

Kasuya

et al. 2014

The Journal of Immunology

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“…pTregs develop in response to peripheral encounters with antigens such as those from food, microbiota and fetal alloantigens for pregnant females [18][19][20][21][22]. Thus tTregs and pTregs have distinct repertoires that complement each other to ensure tolerance to self-antigens and the changing environment.…”

Section: Tregs Are Critical Mediators Of Peripheral Tolerancementioning

confidence: 99%

Restoring Regulatory T Cells in Type 1 Diabetes

Spence

Tang

2016

Curr Diab Rep

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“…Given this surprising bias in T-cell differentiation during in vitro differentiation, we performed adoptive transfer experiments to determine their differentiation during homeostatic proliferation. As shown in T cells (22). To determine whether the bias toward FoxP3 expression in FoxP3 − CD4 + T cells in our T138 model is because of an enlarged RTE population, we performed flow cytometric analysis of thymus and spleen.…”

Section: Characterization Of Foxp3mentioning

confidence: 99%

“…6J). Clearly, this poised state in FoxP3 − CD4 + T cells was only evident in mice carrying the nTreg TCR αβ-pair, and was not because of an increase in recent thymic emigrants (22). Given this strong bias in differentiation away from Th1 and toward Treg cells and their expression of an nTregderived TCR, we consider this T-cell subset as peripheral precursors of nTreg cells, and hence refer to these cells as pre-nTreg cells and not conventional CD4 + T cells (Fig.…”

Section: Foxp3mentioning

confidence: 99%

Nuclear transfer nTreg model reveals fate-determining TCR-β and novel peripheral nTreg precursors

Ku¹,

Chang²,

Hernández³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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To study the development and function of "natural-arising" T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3 + CD4 + Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) β-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR β-chain was able to provide stronger TCR signals. This TCR-β-driven mechanism would thus unify former per se contradicting hypotheses of TCR-dependent and -independent nTreg development. Strikingly, peripheral FoxP3 − CD4 + T cells expressing the same TCR as this somatic cell nuclear transfer nTreg model had a reduced capability to differentiate into Th1 cells but were poised to differentiate better into induced nTreg cells, both in vitro and in vivo, representing a novel peripheral precursor subset of nTreg cells to which we refer to as pre-nTreg cells. ). The development and selection of nTreg cells in the thymus has been the subject of scientific debates for decades, and two contradicting hypotheses have been formulated. Although one hypothesis emphasized the development of nTreg cells in a T-cell receptor (TCR)-dependent manner, the other hypothesis postulated a TCR-independent mechanism. The TCR-dependent development is supported by the observation that TCR transgenic models generated from non-Treg cells did not possess any nTreg cells (7). In line with the TCR-dependent hypothesis is the notion that Treg cells developed in non-Treg TCR transgenic models only when the cognate antigen was expressed in the thymus (8-10). The TCR-independent hypothesis was proposed based on the observation that nTreg development was favored in a subset of CD4 − CD8 − double-negative (DN) cells before the expression of a full TCR on the surface, and that development of Treg cells was less affected than that of conventional CD4+ T cells in pre-TCR-α −/− (pTα) mice (11,12). Given that the pTα, together with TCR-β, is expressed as pre-TCR at the CD4 CD8 DN stage 3 (DN3) before selection at the CD4 CD8 double-positive (DP) stage, a TCR-independent Treg development was indicated. In addition, although some studies investigating the TCR repertoire of conventional T cells (Tconv) and Treg cells demonstrated a partial overlap in support of the TCR-independent hypothesis, other studies reported no gross similarity of the TCR repertoire, in line with a TCR-dependent development (13-15).TCR transgenic mice have been valuable tools in better understanding the role of T cells in health and disease. Several mouse models had been made to study the development and function of nTreg cells. First studies used existing non-Treg TCR transgenic mice and expressed the cognate antigen in the thymus...

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Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery

Cited by 73 publications

References 42 publications

Homeostasis of Thymus-Derived Foxp3+ Regulatory T Cells Is Controlled by Ultraviolet B Exposure in the Skin

Homeostasis of Thymus-Derived Foxp3+ Regulatory T Cells Is Controlled by Ultraviolet B Exposure in the Skin

Restoring Regulatory T Cells in Type 1 Diabetes

Nuclear transfer nTreg model reveals fate-determining TCR-β and novel peripheral nTreg precursors

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