Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells

Weiss, Jonathan M.; Bilate, Angelina M.; Gobert, Michael; Ding, Yi; Lafaille, Maria A. Curotto de; Parkhurst, Christopher N.; Xiong, Huizhong; Dolpady, Jayashree; Frey, Alan B.; Ruocco, Maria Grazia; Yang, Yi; Floess, Stefan; Huehn, Jochen; Oh, Soyoung; Li, Ming O.; Niec, Rachel; Rudensky, Alexander Y.; Dustin, Michael L.; Littman, Dan R.; Lafaille, Juan J.

doi:10.1084/jem.20120914

Cited by 542 publications

(552 citation statements)

References 69 publications

(104 reference statements)

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“…Up to now, no solid marker to discriminate thymus-derived and peripherally induced Tregs was found. Recently, Nrp-1 was proposed to be expressed at high levels on thymus-derived opposed to peripherally induced Tregs (40,41). In this study, we found lower H2BeGFP levels in Nrp1 high compared with Nrp1 low Tregs.…”

Section: Discussionsupporting

confidence: 57%

“…Next, we sought to investigate the proliferation history of Treg populations defined by Treg-specific markers. The transcription factor Helios (39) and the surface molecule Nrp1 (40,41) were recently proposed to discriminate thymic-derived and peripherally induced Tregs. As revealed by H2BeGFP levels of the respective Treg populations in secondary lymphoid organs, Helios + and Nrp1 high Tregs had proliferated more than Helios 2 or Nrp1 low Tregs (Fig.…”

Section: Proliferation History Of Peripheral Treg Subsetsmentioning

confidence: 99%

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Differential Postselection Proliferation Dynamics of αβ T Cells, Foxp3+ Regulatory T Cells, and Invariant NKT Cells Monitored by Genetic Pulse Labeling

Föhse

Reinhardt

Oberdörfer

et al. 2013

The Journal of Immunology

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The thymus generates two divergent types of lymphocytes, innate and adaptive T cells. Innate T cells such as invariant NKT cells provide immediate immune defense, whereas adaptive T cells require a phase of expansion and functional differentiation outside the thymus. Naive adaptive T lymphocytes should not proliferate much after positive selection in the thymus to ensure a highly diverse TCR repertoire. In contrast, oligoclonal innate lymphocyte populations are efficiently expanded through intrathymic proliferation. For CD4+Foxp3+ regulatory T cells (Tregs), which are thought to be generated by agonist recognition, it is not clear whether they proliferate upon thymic selection. In this study, we investigated thymic and peripheral T cell proliferation by genetic pulse labeling. To this end, we used a mouse model in which all developing αβ thymocytes were marked by expression of a histone 2B–enhanced GFP (H2BeGFP) fusion-protein located within the Tcrd locus (TcrdH2BeGFP). This reporter gene was excised during TCR α-chain VJ-recombination, and the retained H2BeGFP signal was thus diluted upon cell proliferation. We found that innate T cells such as CD1d-restricted invariant NKT cells all underwent a phase of intense intrathymic proliferation, whereas adaptive CD4+ and CD8+ single-positive thymocytes including thymic Tregs cycled, on average, only once after final selection. After thymic exit, retention or loss of very stable H2BeGFP signal indicated the proliferative history of peripheral αβ T cells. There, peripheral Tregs showed lower levels of H2BeGFP compared with CD4+Foxp3− T cells. This further supports the hypothesis that the Treg repertoire is shaped by self-Ag recognition in the steady-state.

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Section: Discussionsupporting

confidence: 57%

Section: Proliferation History Of Peripheral Treg Subsetsmentioning

confidence: 99%

Differential Postselection Proliferation Dynamics of αβ T Cells, Foxp3+ Regulatory T Cells, and Invariant NKT Cells Monitored by Genetic Pulse Labeling

Föhse

Reinhardt

Oberdörfer

et al. 2013

The Journal of Immunology

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“…Although Nrp-1 was initially proposed as a naturally occurring T reg -cell-specific marker (14,17), additional studies have shown that peripherally induced T reg cells are capable of up-regulating Nrp-1, especially in the lung (18,19). Consequently, it remains uncertain whether the expanded T reg cells in the lungs of BeOexposed HLA-DP2 Tg mice are naturally occurring or peripherally induced.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

Mack¹,

Falta²,

McKee³

et al. 2014

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

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Susceptibility to chronic beryllium disease (CBD) is linked to certain HLA-DP molecules, including HLA-DP2. To elucidate the molecular basis of this association, we exposed mice transgenic (Tg) for HLA-DP2 to beryllium oxide (BeO) via oropharyngeal aspiration. As opposed to WT mice, BeO-exposed HLA-DP2 Tg mice developed mononuclear infiltrates in a peribronchovascular distribution that were composed of CD4 + T cells and included regulatory T (T reg ) cells. Beryllium-responsive, HLA-DP2-restricted CD4 + T cells expressing IFN-γ and IL-2 were present in BeO-exposed HLA-DP2 Tg mice and not in WT mice. Using Be-loaded HLA-DP2-peptide tetramers, we identified Be-specific CD4 + T cells in the mouse lung that recognize identical ligands as CD4 + T cells derived from the human lung. Importantly, a subset of HLA-DP2 tetramer-binding CD4 + T cells expressed forkhead box P3, consistent with the expansion of antigen-specific T reg cells. Depletion of T reg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation. These findings document, for the first time to our knowledge, the development of a Be-specific adaptive immune response in mice expressing HLA-DP2 and the ability of T reg cells to modulate the beryllium-induced granulomatous immune response.metal hypersensitivity | MHC presentation | genetic susceptibility

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“…We next addressed the physiological relevance of KLF2 by examining peripheral Treg (pTreg) populations under homeostatic conditions. Reports indicate that Helios (an Ikaros transcription factor family member) and Neuropilin 1 (Nrp1, a membrane-bound surface receptor) are preferentially but not exclusively expressed by tTregs relative to pTregs (20)(21)(22)(23)(24)(25). To determine whether either of these molecules were appropriate surrogates for pTreg identification, we initially characterized expression patterns within the entire regulatory Tcell compartment.…”

Section: Klf2 Is Required For the Ex Vivo Generation Of Itregsmentioning

confidence: 99%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

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

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Regulatory T cells (Tregs) are a specialized subset of CD4 + T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.

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Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells

Abstract: Neuropilin-1 surface expression discriminates between nT reg cells with stable expression and Nrp1 low iT reg cells showing inducible expression under inflammatory conditions.

Cited by 542 publications

References 69 publications

Differential Postselection Proliferation Dynamics of αβ T Cells, Foxp3+ Regulatory T Cells, and Invariant NKT Cells Monitored by Genetic Pulse Labeling

Differential Postselection Proliferation Dynamics of αβ T Cells, Foxp3+ Regulatory T Cells, and Invariant NKT Cells Monitored by Genetic Pulse Labeling

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

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