scholarly journals TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets

2007 ◽  
Vol 204 (9) ◽  
pp. 2039-2045 ◽  
Author(s):  
Jamie Wong ◽  
Diane Mathis ◽  
Christophe Benoist
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Nod Mice ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Lineage Tracing ◽  
Peripheral Tolerance ◽  
Cell Conversion ◽  
Endogenous Loci ◽  
Self Antigen

Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4+ T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor β treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by “converting” potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCRα chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the Vα2 family showed their joining CDR3α regions to be very different in T reg and T conv cell thymocytes. These specific CDR3α motifs, thus, provided a “tag” with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3α motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC+Vα2+ cells showed that little to no conversion occurs in response to this pancreatic autoantigen.

scholarly journals WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells

2007 ◽  
Vol 204 (2) ◽  
pp. 369-380 ◽  
Author(s):  
Francesco Marangoni ◽  
Sara Trifari ◽  
Samantha Scaramuzza ◽  
Cristina Panaroni ◽  
Silvana Martino ◽  
...  
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Effector T Cells ◽  
Peripheral Tolerance ◽  
Wild Type ◽  
Suppressor Activity ◽  
Suppressor Function

A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4+CD25+FOXP3+ natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses to self-antigens and allergens. Therefore, we investigated the effect of WAS protein (WASP) deficiency on the distribution and suppressor function of nTreg cells. In WAS−/− mice, the steady-state distribution and phenotype of nTreg cells in the thymus and spleen were normal. However, WAS−/− nTreg cells engrafted poorly in immunized mice, indicating perturbed homeostasis. Moreover, WAS−/− nTreg cells failed to proliferate and to produce transforming growth factor β upon T cell receptor (TCR)/CD28 triggering. WASP-dependent F-actin polarization to the site of TCR triggering might not be involved in WAS−/− nTreg cell defects because this process was also inefficient in wild-type (WT) nTreg cells. Compared with WT nTreg cells, WAS−/− nTreg cells showed reduced in vitro suppressor activity on both WT and WAS−/− effector T cells. Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4+ effector T cells in vitro. Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients.

scholarly journals Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines

2009 ◽  
Vol 206 (10) ◽  
pp. 2131-2139 ◽  
Author(s):  
Jens Nolting ◽  
Carolin Daniel ◽  
Sabine Reuter ◽  
Christina Stuelten ◽  
Peng Li ◽  
...  
Keyword(s):  
T Cells ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Partial Explanation ◽  
Cell Conversion ◽  
Smad3 Expression

It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor α (RARα) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RARα1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RARα2. Interleukin (IL)-6 strongly reduced RARα expression levels such that a deficiency of the predominant RARα1 isoform leaves too little RARα2 for RA to inhibit the generation of Th17 cells in the presence of IL-6.

Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1162-1169 ◽  
Author(s):  
Megan K. Levings ◽  
Silvia Gregori ◽  
Eleonora Tresoldi ◽  
Sabrina Cazzaniga ◽  
Chiara Bonini ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Cellular Therapy ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Peripheral Tolerance ◽  
Immature Dendritic Cells ◽  
Tr1 Cells

Abstract Dendritic cells (DCs) are specialized antigen-presenting cells that monitor the antigenic environment and activate naive T cells. The role of DCs is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. Indeed, if a naive T cell encounters its antigen on immature DCs (iDCs), it may differentiate into a T-regulatory (Tr) rather than a T-effector cell. However, little is known about the mechanisms by which iDCs differentiate Tr cells. We developed a standardized and highly reproducible protocol to differentiate Tr cells by repetitive exposure of naive peripheral blood CD4+ T cells to allogeneic iDCs. The resultant Tr cells are phenotypically and functionally identical to type 1 Tr (Tr1) cells because their generation requires production of IL-10 by iDCs, and they suppress T-cell responses through an interleukin-10 (IL-10)– and a transforming growth factor β (TGF-β)–dependent mechanism. In addition, Tr1 cells induced by iDCs do not require the presence of CD4+CD25+ Tr cells for their generation, nor do they express high constitutive levels of CD25 or the transcription factor FoxP3. Thus, iDCs can drive the differentiation of Tr1 cells and can be used to generate large numbers of alloantigen-specific Tr1 cells for clinical use as a cellular therapy to restore peripheral tolerance.

Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β–treated alloreactive T cells that do not induce graft-versus-host disease

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 565-571 ◽  
Author(s):  
Vassiliki A. Boussiotis ◽  
Zong-Ming Chen ◽  
Jay C. Zeller ◽  
William J. Murphy ◽  
Alla Berezovskaya ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Graft Versus Host

Abstract The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level. Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-β (TGF-β) results in induction of tolerance, rendering alloreactive murine CD4+ T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-β–tolerant CD4+ T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G1 phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGFβ + IL-10–tolerant cells were incapable of phosphorylating TCR-ζ, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27kip1 cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle. These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-β–tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo.

scholarly journals Induction of FOXP3 expression in naive human CD4+FOXP3− T cells by T-cell receptor stimulation is transforming growth factor-β–dependent but does not confer a regulatory phenotype

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2983-2990 ◽  
Author(s):  
Dat Q. Tran ◽  
Heather Ramsey ◽  
Ethan M. Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
T Cell Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
T Regulatory Cell ◽  
Regulatory Phenotype

Abstract Thymic-derived natural T-regulatory cells (nTregs) are important for the induction of self-tolerance and the control of autoimmunity. Murine CD4+CD25−Foxp3− cells can be induced to express Foxp3 after T-cell receptor (TCR) activation in the presence of transforming growth factor β (TGFβ) and are phenotypically similar to nTregs. Some studies have suggested that TCR stimulation of human CD4+CD25− cells results in the induction of transient expression of FOXP3, but that the induced cells lack a regulatory phenotype. We demonstrate here that TCR stimulation alone was insufficient to induce FOXP3 expression in the absence of TGFβ, whereas high levels of FOXP3 expression could be induced in the presence of TGFβ. Although FOXP3 expression was stable, the TGFβ-induced FOXP3+ T cells were neither anergic nor suppressive and produced high levels of effector cytokines. These results suggest that even high levels of FOXP3 expression are insufficient to define a human CD4+ T cell as a T-regulatory cell.

scholarly journals Identification of an immediate Foxp3− precursor to Foxp3+ regulatory T cells in peripheral lymphoid organs of nonmanipulated mice

2010 ◽  
Vol 207 (7) ◽  
pp. 1393-1407 ◽  
Author(s):  
Sonja Schallenberg ◽  
Pei-Yun Tsai ◽  
Julia Riewaldt ◽  
Karsten Kretschmer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Lymphoid Organs ◽  
Minor Role ◽  
A Minor

CD4+CD25+ regulatory T cells (T reg cells) expressing the transcription factor Foxp3 can be induced from peripheral T cell receptor (TCR) transgenic CD4+CD25−Foxp3− T cells stimulated with noninflammatory dendritic cells presenting low amounts of agonist cognate antigen. However, limited evidence exists for extra-thymic T reg cell generation from non-TCR transgenic T cells in unmanipulated mice. We compared events early during agonist-driven generation of Foxp3+ TCR transgenic T cells to polyclonal CD4+ T cell populations in unmanipulated mice. We identified an interleukin-2– and phosphatidylinositol-3-kinase–dependent precommitted Foxp3− precursor to Foxp3+ T reg cells in peripheral lymphoid organs. Transforming growth factor β signaling played a minor role in the generation and subsequent differentiation of these T reg precursor cells.

scholarly journals T-bet is essential for encephalitogenicity of both Th1 and Th17 cells

2009 ◽  
Vol 206 (7) ◽  
pp. 1549-1564 ◽  
Author(s):  
Yuhong Yang ◽  
Jeffrey Weiner ◽  
Yue Liu ◽  
Alan J. Smith ◽  
David J. Huss ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
End Products ◽  
Experimental Autoimmune

The extent to which myelin-specific Th1 and Th17 cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) is controversial. Combinations of interleukin (IL)-1β, IL-6, and IL-23 with transforming growth factor β were used to differentiate myelin-specific T cell receptor transgenic T cells into Th17 cells, none of which could induce EAE, whereas Th1 cells consistently transferred disease. However, IL-6 was found to promote the differentiation of encephalitogenic Th17 cells. Further analysis of myelin-specific T cells that were encephalitogenic in spontaneous EAE and actively induced EAE demonstrated that T-bet expression was critical for pathogenicity, regardless of cytokine expression by the encephalitogenic T cells. These data suggest that encephalitogenicity of myelin-specific T cells appears to be mediated by a pathway dependent on T-bet and not necessarily pathway-specific end products, such as interferon γ and IL-17.

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