Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice

Tang, Qizhi; Adams, Jason Y.; Tooley, Aaron J.; Bi, Mingying; Fife, Brian T.; Serra, Pau; Santamaría, Pere; Locksley, Richard M.; Krummel, Matthew F.; Bluestone, Jeffrey A.

doi:10.1038/ni1289

Cited by 710 publications

(740 citation statements)

References 41 publications

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“…Our current data provide experimental evidence that the immunoregulatory activity of naive-like Treg indeed requires CCR7 expression to traffic through LN, thus enabling inhibition of the priming phase of an immune response. Direct interactions between Treg and DC bearing autoantigens have recently been reported to precede inhibition of T cell activation [37]. Since mature DC also express CCR7 [20], it is tempting to speculate that CCR7 expression supports co-localization of both cell types within the antigen-draining LN; circumstances, where CCR7 expression on both T cells and DC is disabled, could additionally aggravate the functional defects.…”

Section: Discussionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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Foxp3 + CD25 + CD4 + Treg play a fundamental role in the maintenance of self tolerance and the control of inflammatory reactions. Previous data demonstrated a division of labor between naive-and effector/memory-like Treg subsets, which is largely based on their lymph node-recirculating and inflammation-seeking migration behavior, respectively. The chemokine receptor CCR7 is expressed on both types of Treg subsets, albeit at different levels. Whether it fulfills similar or distinct roles in these subsets has not been studied so far. We here show that the recirculation of naive-like Treg through LN and, to some extent, the gut is dependent on CCR7. Lack of CCR7 not only prevents recirculation, but also almost completely abolishes the ability of naive-like Treg to control the priming phase of an immune response. In contrast, CCR7 deficiency in effector/memory-like Treg promotes their accumulation in inflamed sites, compatible with a role of CCR7 for exit from the tissue. Local Treg accumulation was accompanied by an enhanced suppression of inflammation. Together, our findings provide conclusive evidence that CCR7 expression on Treg differentially controls in vivo function of the naive-and effector/memory-like subsets.

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Section: Discussionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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“…Peripheral blood was obtained from patients with various subtypes of CLE (SCLE, DLE, LET) (n ϭ 12) as well as from normal healthy donors (n ϭ 18) and separated by Ficoll gradient centrifugation. The detection of Treg by analysis of CD4ϩ,CD25 high cells has produced conflicting results in patients with SLE (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)31,32). Therefore, we used a new intracellular staining method to directly visualize Foxp3ϩ Treg by flow cytometry, which was performed according to the manufacturer's protocol, as described previously (25).…”

Section: Methodsmentioning

confidence: 99%

“…Treg can suppress conventional T cells (Tcon) by direct cell contact in vitro (8), but down-modulation of dendritic cell (DC) function and secretion of inhibitory cytokines, such as interleukin-10 (IL-10) and transforming growth factor ␤ (TGF␤), might contribute to Treg function in vivo (10,11). A major unanswered question about Treg-mediated suppression concerns the location at which tolerance induction occurs in vivo.…”

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confidence: 99%

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Franz¹,

Fritzsching²,

Riehl³

et al. 2007

Arthritis & Rheumatism

123

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Objective. To define the phenotype and function of CD4؉,CD25؉ regulatory T cells (Treg) in patients with cutaneous lupus erythematosus (CLE), a heterogeneous autoimmune disease characterized primarily by inflammatory skin lesions.Methods. The number of Treg in skin specimens obtained from patients with various subtypes of CLE was investigated by immunohistochemical analysis, using anti-Foxp3 and anti-CD4 monoclonal antibodies. Furthermore, characterization of peripheral blood CD4؉,CD25؉ Treg from normal healthy donors and patients with CLE was carried out by flow cytometry, analyzing the expression of Foxp3 and Treg subpopulations. We also purified CD4؉,CD25 high Treg obtained from patients with CLE and tested the sensitivity of these cells to CD95L-mediated apoptosis.Results. Quantitative analysis of CD4؉ T cells in skin lesions from patients with CLE revealed that the number was similar to that in lesions from patients with other chronic inflammatory diseases, but the number of Foxp3؉ Treg in CLE was significantly reduced. There was no correlation between disease subtype and the frequency of Foxp3؉ Treg in the skin of patients with CLE. In peripheral blood, no significant differences were observed in the number and phenotype of CD4؉,CD25؉ Treg or in the sensitivity to apoptosis of CD4؉,CD25 high Treg derived from patients with CLE and those derived from normal healthy donors.Conclusion. These data suggest that an organspecific abnormality of Treg in the skin underscores the importance of analyzing Treg in the affected tissue. Such a local process might give insight into the pathogenic mechanisms of CLE and differs from a global peripheral dysfunction as reported for patients with a systemic manifestation of the disease.

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“…However, a few antigen-specific Tregs have been identified so far, most likely due to hitherto inadequate technical tools (e.g., MHC class II tetramer assays). Studies in mice have demonstrated that antigen-specific Tregs show a superior immunosuppressive activity as compared to nonspecific Tregs [81,82]. Wang et al were the first to isolate human tumor-associated antigen (TAA)-specific Tregs, in particular Tregs that were specific for the cancer/testis antigen LAGE1 among the TILs of melanoma patients [83].…”

Section: Specificity Of Tregsmentioning

confidence: 99%

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Tanchot

Terme

Péré

et al. 2012

Cancer Microenvironment

119

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In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3 + regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4 + cells.

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Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice

Cited by 710 publications

References 41 publications

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

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