CD4+CD25+ Immunoregulatory T Cells

Regulatory T cells that express the Foxp3 transcription factor play important roles in preventing autoimmune diseases. Although several studies have demonstrated that the lack of the forkhead DNA-binding domain of Foxp3 caused severe autoimmune disease in scurfy mutant mice, the other functional domains of Foxp3 are less well characterized. Here, we show that the deletion of glutamic acid (⌬E250) in the leucine-zipper domain of Foxp3 causes a loss of hyporesponsiveness when compared with wild-type Foxp3 upon antigenic stimulation. CD4 T cells that ectopically express the glutamic acid mutant show significant losses of suppressor activity both in vitro and in vivo. We also demonstrate that regulation of both Th1-and Th2-type cytokine secretion in CD4 T cells that express wild-type Foxp3 is significantly altered by the deletion of glutamic acid. Defects are also observed in the expression of adhesion molecules, such as L-selectin (CD62L) and CD103, suggesting an important role of glutamic acid in the migratory behavior of regulatory T cells. Finally, this mutation reduces transcriptional repressor activity and impairs the homodimerization of Foxp3. Taken together, our results provide insight into the mechanism that controls autoimmune diseases via the deletion of this single glutamic acid residue in the leucine-zipper domain of Foxp3. autoimmunity R egulatory T cells are known to play key roles in the maintenance of immunological homeostasis by the suppression of potential self-reactive CD4ϩCD25Ϫ T cells in the periphery (1). Naturally arising CD4ϩCD25ϩ T cells isolated from both mouse and human show similar behaviors in terms of potent suppressive functions on their CD25Ϫ counterparts via cell-cell contact (2, 3).Recent studies on CD4ϩCD25ϩ T cells have shown that Foxp3, a forkhead (FKH) family transcription factor, has an important role in regulatory T cell development and is currently the best lineage marker in mice (4). In addition, Foxp3-expressing regulatory T cells themselves are hyporesponsive to antigenic stimulation for both proliferation and inhibition of cytokine secretion (4, 5). Transgenic and knockout studies of Foxp3 revealed that Foxp3 plays a critical role for the prevention of autoimmune disease, adoptive transfer of Foxp3-expressing CD4 T cells have also demonstrated that ectopic expression of Foxp3 is sufficient for the mediation of immunological tolerance in vivo (5-7).In humans, it has been shown that Foxp3 mutations are responsible for Ϸ70% of patients with severe X-linked autoimmunity and allergic disorders in immune dysfunction polyendocrinopathy enteropathy X-linked (IPEX). The onset of similar autoimmune disease occurs in scurfy mutant mice that lacks the important FKH-binding domain in Foxp3 because of the presence of a 2-bp insertion that results in an early stop codon (8-10). Although members of the Fox family can act as transcriptional activators and repressors, it has been shown experimentally that the FKH domain of Foxp3 is required for the suppression of various cytokine genes (1...

Section: Deletion Of Glutamic Acid In Foxp3 Inhibits Induction Of Celmentioning

confidence: 79%

The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells

Chae

Henegariu

Lee

et al. 2006

“…With sufficient IL-2 to counteract its suppressive effects, TGF-␤ enhances the proliferation and survival of human T cells that develop potent suppressive activities (29). Moreover, engagement of GITR on CD4 ϩ CD25 ϩ regulatory T cells seems able to lead to an intermediate step of reversal anergy where IL-2-induced proliferation may occur (35,36). Engagement of both GITR and TGF-␤ engagement may therefore allow proliferation of regulatory T cells while preserving their suppressive activity.…”

Section: Discussionmentioning

confidence: 99%

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

Peng

Laouar

et al. 2004

381

272

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...

“…GITR engagement in the presence of suboptimal T cell receptor stimulation generates a positive costimulatory signal leading to increased T cell proliferation and cytokine production (6)(7)(8). More importantly, GITR stimulation on effector T cells has been shown to reverse the suppressive effects by the Tregs in mice (7,9,10). The GITRL:GITR pathway thus provides a potential target for manipulating T cell responsiveness to clear infectious pathogens and tumors and to reverse globally suppressed immune responses resulting from chronic infections.…”

mentioning

confidence: 99%

Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily

Chattopadhyay

Ramagopal²,

Brenowitz³

et al. 2008

Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique ''domain-swapping'' interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution. Structureguided mutagenesis studies confirmed the determinants responsible for dimerization and support a previously unrecognized receptor-recognition surface for mouse GITRL that has not been observed for any other TNF family members. Taken together, the unique structural and biochemical behavior of mouse GITRL, along with the unusual domain organization of murine GITR, support a previously unrecognized mechanism for signaling within the TNF superfamily.crystal structure ͉ domain swap ͉ oligomerization ͉ T cell costimulation