CD4+CD25+regulatory T cells generated in response to insulin B:9–23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells

Mukherjee, Rinee; Chaturvedi, Pratibha; Qin, Hui‐Yu; Singh, Bhagirath

doi:10.1016/s0896-8411(03)00114-8

Cited by 75 publications

(54 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To determine whether these cells with a regulatory T cell phenotype are endowed with suppressive activity in vivo, an adoptive transfer model was used that is commonly applied toward this end (28). Intraislet T cells were isolated from transgenic or control mice and then cotransferred with splenic cells from diabetic NOD mice into NOD-SCID recipient mice (Fig.…”

Section: Tgf-␤ Promotes Expansion Of the Foxp3-expressing Cd4mentioning

confidence: 99%

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Peng

Laouar

et al. 2004

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

382

273

View full text Add to dashboard Cite

CD4 ؉ CD25 ؉ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor ␤ (TGF-␤) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4 ؉ CD25 ؉ T cell pool. Approximately 40 -50% of intraislet CD4 ؉ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF-␤ expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-␤ inhibits autoimmune diseases via regulation of the size of the CD4 ؉ CD25 ؉ regulatory T cell pool in vivo.T ype I diabetes is an autoimmune disease that results from the failure of tolerance to beta-cell antigens (1). The mechanisms that have evolved to ensure discrimination between self and nonself are highly complex and not foolproof. Models of passive tolerance, such as thymic deletion of autoreactive T cells or nonreponsiveness in the periphery because of anergy or ignorance, cannot account for the presence of autoreactive T cells in healthy individuals despite the absence of the development of organ-specific autoimmune diseases. T cells endowed with suppressive function to control actions of autoreactive T cells were described decades ago and were thought originally to be a specialized T cell population the effect of which would be mediated by secreted antigen-specific factors (2). Nowadays, suppressor T cells (also referred to as regulatory T cells) are delineated into two cell subsets of natural regulatory (CD4 ϩ CD25 ϩ ) cells that emerge from the thymus (3, 4) and adaptive regulatory (CD4 ϩ CD25 Ϫ ) cells induced in the periphery to develop suppressive activity (5-7). However, this concept of dichotomous thymic CD25 ϩ versus adaptive CD25 Ϫ regulatory T cells has been challenged by several reports, supporting evidence for the peripheral generation of CD25 ϩ regulatory T cells in vivo and in vitro (8)(9)(10)(11)(12). The finding that suppressive functions are instructively programmed by the expression of Foxp3 finally provided the basis for integrating a unified model of regulatory T cell diversity (13-15). Forced expression of Foxp3 in CD4 ϩ CD25 Ϫ nonregulatory T cells, either by retroviral expression or in transgenic mice, showed acquisition of suppressive activity in vitro and inhibition of disease in vivo, inducing in a substantial proportion of Foxp3-bearing cells the expression of CD25 and GITR markers indicating that ex...

show abstract

Section: Tgf-␤ Promotes Expansion Of the Foxp3-expressing Cd4mentioning

confidence: 99%

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Peng

Laouar

et al. 2004

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

382

273

View full text Add to dashboard Cite

show abstract

“…Additionally, prophylactic treatment with CD4ϩ,CD25ϩ regulatory T cells has been reported to diminish the severity of other T cell-mediated autoimmune diseases, such as experimental autoimmune encephalomyelitis (14) and diabetes (15).…”

mentioning

confidence: 99%

Effective treatment of collagen‐induced arthritis by adoptive transfer of CD25+ regulatory T cells

Morgan¹,

Flierman²,

Duivenvoorde³

et al. 2005

Arthritis & Rheumatism

358

244

View full text Add to dashboard Cite

Objective. Regulatory T cells play an important role in the prevention of autoimmunity and have been shown to be effective in the treatment of experimental colitis, a T cell-mediated and organ-specific disease. We previously demonstrated that intrinsic CD25؉ regulatory T cells modulate the severity of collagen-induced arthritis (CIA), which, in contrast to colitis, is a systemic antibody-mediated disease and an accepted model of rheumatoid arthritis. We undertook this study to determine whether regulatory T cells have the potential to be used therapeutically in arthritis.Methods. We transferred CD4؉,CD25؉ T cells into mice exhibiting arthritis symptoms, both immunocompetent mice and mice subjected to lethal irradiation and rescued with syngeneic bone marrow transplantation.Results. A single transfer of regulatory T cells markedly slowed disease progression, which could not be attributed to losses of systemic type II collagenspecific T and B cell responses, since these remained unchanged after adoptive transfer. However, regulatory T cells could be found in the inflamed synovium soon after transfer, indicating that regulation may occur locally in the joint. Conclusion.Our data indicate that CD25؉ regulatory T cells can be used for the treatment of systemic, antibody-mediated autoimmune diseases, such as CIA.

show abstract

“…Transfer experiments indicated inhibition of disease transfer by splenocytes from ␣-chain-only transgenics consistent with induction of regulation. Immunization with insulin peptide B:9-23 of NOD mice induces a similar phenotype with induction of high titers of insulin autoantibodies and diabetes prevention (19,24). The 12-4.1 ␣-chain may also regulate islet autoimmunity when coupled with different ␤-chains.…”

Section: Discussionmentioning

confidence: 99%

Conserved T cell receptor α-chain induces insulin autoantibodies

Kobayashi

Jasinski

Liu

et al. 2008

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

View full text Add to dashboard Cite

A fundamental question is what are the molecular determinants that lead to spontaneous preferential targeting of specific autoantigens in autoimmune diseases, such as the insulin B:9 -23 peptide sequence in type 1 diabetes. Anti-insulin B:9 -23 T cell clones isolated from prediabetic NOD islets have a conserved V␣-segment/J␣-segment, but no conservation of the ␣-chain N region and no conservation of the V␤-chain. Here, we show that the conserved T cell receptor ␣-chain generates insulin autoantibodies when transgenically or retrogenically introduced into mice without its corresponding V␤. We suggest that a major part of the mystery as to why islet autoimmunity develops relates to recognition of a primary insulin peptide by a conserved ␣ chain T cell receptor.autoimmunity ͉ NOD mouse ͉ Type 1 diabetes ͉ retrogenic

show abstract

CD4+CD25+regulatory T cells generated in response to insulin B:9–23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells

Cited by 75 publications

References 72 publications

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Effective treatment of collagen‐induced arthritis by adoptive transfer of CD25+ regulatory T cells

Conserved T cell receptor α-chain induces insulin autoantibodies

Contact Info

Product

Resources

About

CD4+CD25+regulatory T cells generated in response to insulin B:9–23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells

Cited by 75 publications

References 72 publications

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4+CD25+regulatory T cells responsible for protection against diabetes

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4+CD25+regulatory T cells responsible for protection against diabetes

Effective treatment of collagen‐induced arthritis by adoptive transfer of CD25+ regulatory T cells

Conserved T cell receptor α-chain induces insulin autoantibodies

Contact Info

Product

Resources

About

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes