Molecular orchestration of differentiation and function of regulatory T cells

Lu, Li-Fan; Rudensky, Alexander Y.

doi:10.1101/gad.1791009

Cited by 78 publications

(86 citation statements)

References 141 publications

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“…As Tregs play a critical role in peripheral T cell tolerance (21) and PEP-deficient mice had increased total Treg numbers (22), we determined whether the variant altered Treg development and/or function. Expression of PEP-R619W did not affect Treg development or absolute numbers in lymphoid organs in young (6 to 8 weeks) mice.…”

Section: Resultsmentioning

confidence: 99%

A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

et al. 2013

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Multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus, are associated with an allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), which encodes the protein LYP. To model the human disease-linked variant LYP-R620W, we generated knockin mice expressing the analogous mutation, R619W, in the murine ortholog PEST domain phosphatase (PEP). In contrast with a previous report, we found that this variant exhibits normal protein stability, but significantly alters lymphocyte function. Aged knockin mice exhibited effector T cell expansion and transitional, germinal center, and age-related B cell expansion as well as the development of autoantibodies and systemic autoimmunity. Further, PEP-R619W affected B cell selection and B lineage-restricted variant expression and was sufficient to promote autoimmunity. Consistent with these features, PEP-R619W lymphocytes were hyperresponsive to antigen-receptor engagement with a distinct profile of tyrosine-phosphorylated substrates. Thus, PEP-R619W uniquely modulates T and B cell homeostasis, leading to a loss in tolerance and autoimmunity.

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Section: Resultsmentioning

confidence: 99%

A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

et al. 2013

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“…The vast majority of research to date has implicated Tregs in suppressing antigen-driven and T cell-dependent adaptive immune responses, especially in models of autoimmunity, infections, and cancer (reviewed in refs. 22,23). In these diseases, Tregs are thought to be activated in an antigen-dependent manner and to inhibit self-reactive or pathogenic T cells through multiple mechanisms, including contact-dependent inhibitory cell surface receptors (e.g., CTLA-4), secretion of inhibitory cytokines (e.g., IL-10 and TGF-β), competition for growth factors (e.g., IL-2), and potentially direct lysis (24).…”

Section: Resolution Of Lung Injurymentioning

confidence: 99%

Resolving lung injury: a new role for Tregs in controlling the innate immune response

Pietropaoli

Georas²

2009

J. Clin. Invest.

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“…Upon stimulation, naive CD4 + T cells differentiate into effector Th cells (1). Foxp3 + Tregs represent a unique subpopulation of CD4 + T cells that are important for maintenance of immunological homeostasis and self tolerance (2,3). Naive T cells circulate between blood and secondary lymphoid tissues (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Tomura

Honda²,

Tanizaki³

et al. 2010

J. Clin. Invest.

251

302

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Tregs play an important role in protecting the skin from autoimmune attack. However, the extent of Treg trafficking between the skin and draining lymph nodes (DLNs) is unknown. We set out to investigate this using mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light. By exposing the skin of Kaede-transgenic mice to violet light, we were able to label T cells in the periphery under physiological conditions with Kaede-red and demonstrated that both memory phenotype CD4 + Foxp3 -non-Tregs and CD4 + Foxp3 + Tregs migrated from the skin to DLNs in the steady state. During cutaneous immune responses, Tregs constituted the major emigrants and inhibited immune responses more robustly than did LN-resident Tregs. We consistently observed that cutaneous immune responses were prolonged by depletion of endogenous Tregs in vivo. In addition, the circulating Tregs specifically included activated CD25 hi Tregs that demonstrated a strong inhibitory function. Together, our results suggest that Tregs in circulation infiltrate the periphery, traffic to DLNs, and then recirculate back to the skin, contributing to the downregulation of cutaneous immune responses.

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Molecular orchestration of differentiation and function of regulatory T cells

Cited by 78 publications

References 141 publications

A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models

Resolving lung injury: a new role for Tregs in controlling the innate immune response

Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

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