Mitigation of Experimental Allergic Encephalomyelitis by TGF-β Induced Foxp3+ Regulatory T Lymphocytes through the Induction of Anergy and Infectious Tolerance

Selvaraj, Ramesh K.; Geiger, Terrence L.

doi:10.4049/jimmunol.180.5.2830

Cited by 109 publications

(114 citation statements)

References 58 publications

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“…Therefore, a local regulatory activity of T reg in inflamed tissue in the brain is very unlikely. However, the principal ability of T reg to be retained in the brain was demonstrated in the experimental autoimmune encephalomyelitis model (25). This indicates that the homing capacities of T reg vary in different disease settings, which might also influence the outcome of the immune response (26).…”

Section: Discussionmentioning

confidence: 99%

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Steeg

Adler

Sparwasser

et al. 2009

The Journal of Immunology

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Cerebral malaria (CM) associated with Plasmodium berghei ANKA (PbA) infection is an accepted model of human CM. CM during PbA infection critically depends on sequestration of T cells into the brain. Several studies aimed to address the role of regulatory T cells (Treg) in modulating this pathogenic T cell response. However, these studies are principally hampered due to the fact that until recently no reagents were available to deplete Foxp3+ Treg specifically. To study the function of Treg in the genesis of CM, we used depletion of Treg mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin receptor-enhanced GFP fusion protein under the control of the foxp3 gene locus. These mice allow for a selective depletion of Foxp3+ Treg by diphtheria toxin injection, and also their specific detection and purification during an ongoing infection. Using depletion of Treg mice, we found only a small increase in the absolute numbers of Foxp3+ Treg during PbA infection and, consequently, the ratio of Treg to T effector cells (Teff) decreased due to the rapid expansion of Teff. Although the latter sequester in the brains of infected mice, almost no Treg were found in the brains of infected mice. Furthermore, we demonstrate that depletion of Treg has no influence on sequestration of Teff and on the clinical outcome, and only minor influence on T cell activation. Using ex vivo analysis of purified Treg from either naive mice or PbA-infected mice, we found that both exhibit similar inhibitory capacity on Teff.

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Section: Discussionmentioning

confidence: 99%

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Steeg

Adler

Sparwasser

et al. 2009

The Journal of Immunology

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“…The role of Treg or Foxp3 has been studied in various autoimmune disease models such as inflammatory bowel disease (IBD) (13,14), experimental allergic encephalomyelitis (15,16), and arthritis (17). Transfer of CD4 + CD25 + Tregs completely inhibits development of these autoimmune diseases, and in vitro expansion methods of Tregs have been developed for use in clinical trials (18)(19)(20).…”

mentioning

confidence: 99%

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

Choi

Shin

Sohn

et al. 2010

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

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Foxp3 is a key transcription factor for differentiation and function of regulatory T (Treg) cells that is critical for maintaining immunological self-tolerance. Therefore, increasing Treg function by Foxp3 transduction to regulate an inflammatory immune response is an important goal for the treatment of autoimmune and allergic diseases. Here we have generated a cell-permeable Foxp3 protein by fusion with the unique human HHph-1-PTD (protein transduction domain), examined its regulatory function in T cells, and characterized its therapeutic effect in autoimmune and allergic disease models. HHph-1-Foxp3 was rapidly and effectively transduced into cells within 30 min and conferred suppressor function to CD4 + CD25 − T cells as well as directly inhibiting T-cell activation and proliferation. Systemic delivery of HHph-1 Foxp3 remarkably inhibited the autoimmune symptoms of scurfy mice and the development of colitis induced by scurfy or wild-type CD4 T cells. Moreover, intranasal delivery of HHph-1-Foxp3 strongly suppressed ovalbumin-induced allergic airway inflammation. These results demonstrate the clinical potential of the cell-permeable recombinant HHph-1-Foxp3 protein in autoimmune and hypersensitive allergic diseases.

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“…In vitro generation of autologous Treg cells could be a treatment option for multiple autoimmune diseases, including experimental autoimmune encephalomyelitis, diabetes, colitis, and lupus (54)(55)(56). However, this approach is quite challenging because it is difficult to generate and/or expand Treg cells with specific Ag specificity, especially when the immunodominant epitopes are uncharacterized, such as in RA.…”

Section: Discussionmentioning

confidence: 99%

Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity

Vicente

Quentin

Mausset-Bonnefont

et al. 2016

The Journal of Immunology

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Promising immunotherapeutic strategies are emerging to restore tolerance in autoimmune diseases by triggering an increase in the number and/or the function of endogenous regulatory T (Treg) cells, which actively control pathological immune responses. Evidence suggests a remarkable heterogeneity in peripheral Treg cells that warrants their better characterization in terms of phenotype and suppressive function, to determine which subset may be optimally suitable for a given clinical situation. We found that repetitive injections of immature dendritic cells expanded Foxp3-negative CD49b+ Treg cells that displayed an effector memory phenotype. These expanded Treg cells were isolated ex vivo for transcriptome analysis and found to contain multiple transcripts of the canonical Treg signature shared mainly by CD25+ but also by other subphenotypes. We characterized the CD49b+ Treg cell phenotype, underscoring its similarities with the CD25+ Treg cell phenotype and highlighting some differential expression patterns for several markers, including lymphocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B. Comparison of the CD25+ and CD49b+ Treg cells' suppressive mechanisms, in vitro and in vivo, revealed the latter's potent suppressive activity, which was partly dependent on IL-10 secretion. Altogether, our results strongly suggest that expression of several canonical Treg cell markers and suppressive function could be Foxp3 independent, and underscore the therapeutic potential of IL-10–secreting CD49b+ Treg cells in arthritis.

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Mitigation of Experimental Allergic Encephalomyelitis by TGF-β Induced Foxp3+ Regulatory T Lymphocytes through the Induction of Anergy and Infectious Tolerance

Cited by 109 publications

References 58 publications

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity

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