Integrated T‐cell receptor and costimulatory signals determine TGF‐β‐dependent differentiation and maintenance of Foxp3<sup>+</sup> regulatory T cells

Gabryšová, Leona; Christensen, Jillian R.; Wu, Xuemei; Kissenpfennig, Adrien; Malissen, Bernard; O’Garra, Anne

doi:10.1002/eji.201041073

Cited by 83 publications

(92 citation statements)

References 37 publications

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“…Monitoring the response of anti-minor histocompatibility Y antigen (HY) TCR transgenic (tg) cells to broad-range titration of their nominal peptide (Fig. 5A) confirmed that the lower the TCR triggering, the larger the frequency of cells acquiring Foxp3 expression (26,27). More importantly, the slope of the dose-response obtained in thymocyte cultures was much steeper than the slope in peripheral cells, indicating differential -recipient mice received 0.1 mg OVA or PBS i.v.…”

Section: Peripheral T-cell Maturation Associates With Altered Sensitimentioning

confidence: 77%

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

Paiva

Lino

Bergman

et al. 2013

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

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Most Forkhead box P3+ (Foxp3 + ) CD4 regulatory T cell (Treg) precursors are newly formed thymocytes that acquire Foxp3 expression on antigen encounter in the thymus. Differentiation of Treg, however, can also occur in the periphery. What limits this second layer of self-and nonself-reactive Treg production in physiological conditions remains to be understood. In this work, we tested the hypothesis that, similarly to thymic Treg, the precursors of peripheral Treg are immature T cells. We show that CD4 Foxp3− thymocytes and recent thymic emigrants (RTEs), contrarily to peripheral naïve mature cells, efficiently differentiate into Treg on transfer into lymphopenic mice. By varying donor and recipient mice and conducting ex vivo assays, we document that the preferential conversion of newly formed T cells does not require intrathymic preactivation, is cell-intrinsic, and correlates with low and high sensitivity to natural inhibitors and inducers of Foxp3 expression, such as IL-6, T-cell receptor triggering, and TGF-β. Finally, ex vivo analysis of human thymocytes and peripheral blood T cells revealed that human RTE and newly developed T cells share an increased potential to acquire a FOXP3 bright CD25high Treg phenotype. Our findings indicating that RTEs are the precursors of Tregs differentiated in the periphery should guide the design of Treg-based therapies.tolerance | development | lymphopoiesis | polarization

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Section: Peripheral T-cell Maturation Associates With Altered Sensitimentioning

confidence: 77%

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

Paiva

Lino

Bergman

et al. 2013

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

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“…Studies have shown that MEK inhibition induces Foxp3 + Tregs (34,35). These findings were not confirmed (Figure 4), which could be attributed to the complexity of the murine BMT models.…”

Section: Discussionmentioning

confidence: 89%

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Itamura¹,

Shindo²,

Tawara³

et al. 2016

JCI Insight

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“…4b). Two groups have recently described that suboptimal activation of CD4 T N cells in the absence of exogenous TGFb led to their conversion into iTreg cells 27,28 . In this setting, a more efficient conversion was also observed in Ly-6C À CD4 T N -cell cultures ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells

et al. 2013

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Upon activation, naive CD4 T cells differentiate into a variety of T-helper-cell subsets characterized by different cytokine production and functions. Currently, lineage commitment is considered to depend mostly on the environmental context to which naive CD4 T cells are exposed. Here we challenge this model based on the supposed homogeneity of the naive CD4 T-cell compartment. We show that peripheral naive CD4 T cells can be subdivided into two subsets according to Ly-6C expression. Furthermore, the two newly defined subsets (Ly-6C À and Ly-6C þ naive CD4 T cells) are not equal in their intrinsic ability to commit into the induced regulatory T-cell lineage. Finally, phenotypic analysis, imaging and adoptive transfer experiments reveal that Ly-6C expression is modulated by self-recognition, allowing the dichotomization of the naive CD4 T-cell compartment into two cell subsets with distinct self-reactivity. Altogether, our results show that naive CD4 T cells with the highest avidity for self are prone to differentiate into regulatory T cells.

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Integrated T‐cell receptor and costimulatory signals determine TGF‐β‐dependent differentiation and maintenance of Foxp3⁺ regulatory T cells

Abstract: Foxp3-expressing Tregs play a non-redundant role in protecting against immune pathologies.

Cited by 83 publications

References 37 publications

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

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

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells

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Integrated T‐cell receptor and costimulatory signals determine TGF‐β‐dependent differentiation and maintenance of Foxp3+ regulatory T cells

Abstract: Foxp3-expressing Tregs play a non-redundant role in protecting against immune pathologies.

Cited by 83 publications

References 37 publications

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

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

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells

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Product

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Integrated T‐cell receptor and costimulatory signals determine TGF‐β‐dependent differentiation and maintenance of Foxp3⁺ regulatory T cells