scholarly journals The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

2009 ◽  
Vol 206 (10) ◽  
pp. 2079-2089 ◽  
Author(s):  
Luisa Klotz ◽  
Sven Burgdorf ◽  
Indra Dani ◽  
Kaoru Saijo ◽  
Juliane Flossdorf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Nuclear Receptor ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Physiological Role ◽  
Negative Regulator ◽  
Orphan Receptor ◽  
Th17 Differentiation

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor–related orphan receptor γt (RORγt). We identify the nuclear receptor peroxisome proliferator–activated receptor γ (PPARγ) as a key negative regulator of human and mouse Th17 differentiation. PPARγ activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPARγ involved inhibition of TGF-β/IL-6–induced expression of RORγt in T cells. Pharmacologic activation of PPARγ prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the RORγt promoter in T cells, thus interfering with RORγt transcription. Both T cell–specific PPARγ knockout and endogenous ligand activation revealed the physiological role of PPARγ for continuous T cell–intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPARγ-mediated suppression of Th17 differentiation. In summary, we report a PPARγ-mediated T cell–intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPARγ represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

Identification of a Discrete Subpopulation of T-Cells Over-Expressing HDAC11 with a TH17 Phenotype

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 588-588
Author(s):  
Karrune Woan ◽  
Fengdong Cheng ◽  
Hongwei Wang ◽  
Jennifer Rock-Klotz ◽  
Zi Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Egfp Expression ◽  
In Vivo Models

Abstract Abstract 588 We recently defined a novel role of histone deacetylase 11 (HDAC11), the newest member of the HDAC family, as a negative regulator of IL-10 gene transcription in antigen-presenting cells (APCs).1 To better understand the role of HDAC11 gene expression in immune cells in vivo, we have utilized a BAC (Bacterial artificial chromosome) transgenic mouse in which the EGFP reporter gene was inserted downstream of the HDAC11 promoter region but immediately upstream of the HDAC11 coding sequence (TgHDAC11-EGFP mice).2 In the steady-state, macrophages and B-cells isolated from spleen of TgHDAC11-EGFP mice express low levels of HDAC11 as evidenced by a slight shift in EGFP fluorescence from background. In sharp contrast, we identified a discrete population (11.9%) of T-cells over-expressing HDAC11 as demonstrated both by flow cytometry for EGFP and by qRT-PCR for HDAC11, a majority of which were CD4+ T-cells. Sorting of this EGFP+, CD4+ T-cell population confirmed that the increased EGFP expression correlated with an increased HDAC11mRNA expression. Reminiscent of our prior data in APCs, the increased expression of HDAC11 in T-cells was also inversely correlated with IL-10mRNA expression. Further analyses revealed that in the absence of any stimulation or T-cell polarizing conditions, this EGFP positive population expressed significantly elevated levels of ROR-γt and IL-17 mRNA, markers specific for the TH17 subpopulation. Polarization of wild type CD4+ T-cells into functional TH17 cells was associated with reduction of HDAC11 expression, suggesting a potential role for HDAC11 in regulating T-cell function and/or activation, in particular within the TH17 subset. Further support for this regulatory role of HDAC11 has been provided by our additional findings that T-cells devoid of HDAC11 are indeed hyper-reactive in vitro and in in vivo models. 1. Villagra A, et al. Nat Immunol. 2009 Jan;10(1):92-100. 2. Gong S, et al. Nature. 2003 Oct 30;425(6961):917-25. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of Interleukin 10–Producing, Nonproliferating Cd4+ T Cells with Regulatory Properties by Repetitive Stimulation with Allogeneic Immature Human Dendritic Cells

2000 ◽  
Vol 192 (9) ◽  
pp. 1213-1222 ◽  
Author(s):  
Helmut Jonuleit ◽  
Edgar Schmitt ◽  
Gerold Schuler ◽  
Jürgen Knop ◽  
Alexander H. Enk
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Repetitive Stimulation ◽  
Negative Regulator ◽  
Th1 Cells ◽  
Alloreactive T Cells ◽  
Stimulation Of

The functional properties of dendritic cells (DCs) are strictly dependent on their maturational state. To analyze the influence of the maturational state of DCs on priming and differentiation of T cells, immature CD83− and mature CD83+ human DCs were used for stimulation of naive, allogeneic CD4+ T cells. Repetitive stimulation with mature DCs resulted in a strong expansion of alloreactive T cells and the exclusive development of T helper type 1 (Th1) cells. In contrast, after repetitive stimulation with immature DCs the alloreactive T cells showed an irreversibly inhibited proliferation that could not be restored by restimulation with mature DCs or peripheral blood mononuclear cells, or by the addition of interleukin (IL)-2. Only stimulation of T cells with mature DCs resulted in an upregulation of CD154, CD69, and CD70, whereas T cells activated with immature DCs showed an early upregulation of the negative regulator cytotoxic T lymphocyte–associated molecule 4 (CTLA-4). These T cells lost their ability to produce interferon γ, IL-2, or IL-4 after several stimulations with immature DCs and differentiated into nonproliferating, IL-10–producing T cells. Furthermore, in coculture experiments these T cells inhibited the antigen-driven proliferation of Th1 cells in a contact- and dose-dependent, but antigen-nonspecific manner. These data show that immature and mature DCs induce different types of T cell responses: inflammatory Th1 cells are induced by mature DCs, and IL-10–producing T cell regulatory 1–like cells by immature DCs.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

scholarly journals Defective T-Cell Activation Is Associated with Augmented Transforming Growth Factor β Sensitivity in Mice with Mutations in the Sno Gene

2003 ◽  
Vol 23 (15) ◽  
pp. 5446-5459 ◽  
Author(s):  
S. Pearson-White ◽  
M. McDuffie
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Negative Regulator ◽  
Mutant Mice ◽  
T Cell Proliferation ◽  
Receptor Ligation

ABSTRACT The proto-oncogene Sno has been shown to be a negative regulator of transforming growth factor beta (TGF-β) signaling in vitro, using overexpression and artificial reporter systems. To examine Sno function in vivo, we made two targeted deletions at the Sno locus: a 5′ deletion, with reduced Sno protein (hypomorph), and an exon 1 deletion removing half the protein coding sequence, in which Sno protein is undetectable in homozygotes (null). Homozygous Sno hypomorph and null mutant mice are viable without gross developmental defects. We found that Sno mRNA is constitutively expressed in normal thymocytes and splenic T cells, with increased expression 1 h following T-cell receptor ligation. Although thymocyte and splenic T-cell populations appeared normal in mutant mice, T-cell proliferation in response to activating stimuli was defective in both mutant strains. This defect could be reversed by incubation with either anti-TGF-β antibodies or exogenous interleukin-2 (IL-2). Together, these findings suggest that Sno-dependent suppression of TGF-β signaling is required for upregulation of growth factor production and normal T-cell proliferation following receptor ligation. Indeed, both IL-2 and IL-4 levels are reduced in response to anti-CD3ε stimulation of mutant T cells, and transfected Sno activated an IL-2 reporter system in non-T cells. Mutant mouse embryo fibroblasts also exhibited a reduced cell proliferation rate that could be reversed by administration of anti-TGF-β. Our data provide strong evidence that Sno is a significant negative regulator of antiproliferative TGF-β signaling in both T cells and other cell types in vivo.

Molecular profiling of CD3−CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 2969-2983 ◽  
Author(s):  
Marie Ravoet ◽  
Catherine Sibille ◽  
Chunyan Gu ◽  
Myriam Libin ◽  
Benjamin Haibe-Kains ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Chronic Disease ◽  
T Cell ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Major Gene ◽  
Hypereosinophilic Syndrome ◽  
Transforming Growth Factor Β ◽  
T Lymphoma

The clonal CD3−CD4+ T-cell population characterizing lymphocytic variant hypereosinophilic syndrome (L-HES) persists for years, with a subgroup of patients ultimately progressing to T lymphoma. The molecular changes associated with the premalignant clone and the emergence of malignant subclones are unknown, precluding the development of targeted therapy for this HES variant. In this study, we used whole genome arrays to examine gene expression in the CD3−CD4+ T cells and found that 850 genes were differentially regulated during chronic disease compared with CD3+CD4+ T cells from healthy donors. Changes in the expression of 349 genes were altered in association with the clinical progression from chronic L-HES to T lymphoma in 1 patient, with 87 of 349 genes representing further changes in genes whose expression was altered in all chronic disease patients (87 of 850). Array analysis after CD2/CD28-mediated activation revealed that the major gene expression changes observed in the CD3−CD4+ T cells do not reflect activation induced alterations but rather pathways involved in T-cell homeostasis, including transforming growth factor-β signaling, apoptosis, and T-cell maturation, signaling, and migration. Examination of microRNA expression in the CD3−CD4+ T cells from patients with chronic disease identified 23 microRNAs that changed significantly, among which miR-125a further decreased in association with one patient's evolution to T lymphoma.

scholarly journals Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells

2011 ◽  
Vol 208 (1) ◽  
pp. 103-114 ◽  
Author(s):  
Masaaki Murakami ◽  
Yuko Okuyama ◽  
Hideki Ogura ◽  
Shogo Asano ◽  
Yasunobu Arima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Antigen Recognition ◽  
Type I ◽  
Antigen Specificity ◽  
Class Ii Mhc ◽  
Cognate Antigen

Cognate antigen recognition by CD4+ T cells is thought to contribute to the tissue specificity of various autoimmune diseases, particularly those associated with class II MHC alleles. However, we show that localized class II MHC–dependent arthritis in F759 mice depends on local events that result in the accumulation of activated CD4+ T cells in the absence of cognate antigen recognition. In this model, transfer of in vitro polarized Th17 cells combined with the induction of experimental microbleeding resulted in CCL20 production, the accumulation of T cells in the joints, and local production of IL-6. Disease induction required IL-17A production by transferred T cells, IL-6 and CCL20 expression, and STAT3 signaling in type I collagen–expressing cells. Our data suggest a model in which the development of autoimmune disease in F759 mice depends on four events: CD4+ T cell activation regardless of antigen specificity, local events that induce T cell accumulation, enhanced sensitivity to T cell–derived cytokines in the tissue, and activation of IL-6 signaling in the tissue. This model provides a possible explanation for why tissue-specific antigens recognized by activated CD4+ T cells have not been identified in many autoimmune diseases, especially those associated with class II MHC molecules.

scholarly journals Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

2018 ◽  
Author(s):  
Judith F. Ashouri ◽  
Lih-Yun Hsu ◽  
Steven Yu ◽  
Dmitry Rychkov ◽  
Yiling Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Autoimmune Arthritis ◽  
Receptor Signaling ◽  
Tcr Signaling ◽  
Autoreactive T Cells

AbstractHow pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood. We used Nur77—a marker of T cell antigen receptor (TCR) signaling—to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. The T cells with increased autoreactivity, nonetheless had diminished ex vivo inducible TCR signaling, perhaps reflective of adaptive inhibitory mechanisms induced by chronic auto-antigen exposure in vivo. The enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery, which might in part be attributable to a reduced amount of expression of suppressor of cytokine signaling 3 (SOCS3)—a key negative regulator of IL-6 signaling. As a result, the more autoreactive GFPhi CD4 T cells from SKGNur mice were hyper-responsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice, SOCS3 expression was similarly downregulated in RA synovium. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA.Significance StatementHow arthritis-causing T cells trigger rheumatoid arthritis (RA) is not understood since it is difficult to differentiate T cells activated by inflammation in arthritic joints from those activated through their TCR by self-antigens. We developed a model to identify and study antigen-specific T cell responses in arthritis. Nur77—a specific marker of TCR signaling—was used to identify antigen-activated CD4 T cells in the SKG arthritis model and patients with RA. Nur77 could distinguish highly arthritogenic and autoreactive T cells in SKG mice. The enhanced autoreactivity was associated with increased IL-6-receptor-signaling, likely contributing to their arthritogenicity. These data highlight a functional correlate between Nur77 expression, arthritogenic T cell populations, and heightened IL-6 sensitivity in SKG mice with translatable implications for human RA.

scholarly journals The Tyrosine Kinase Tec Regulates Effector Th17 Differentiation, Pathogenicity, and Plasticity in T-Cell-Driven Intestinal Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Lisa Sandner ◽  
Marlis Alteneder ◽  
Ci Zhu ◽  
Anastasiya Hladik ◽  
Sandra Högler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Adoptive Transfer ◽  
Th17 Cells ◽  
Negative Regulator ◽  
Fine Tuning ◽  
T Helper ◽  
Stat3 Phosphorylation ◽  
Th17 Differentiation

T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known as transdifferentiation relying on plasticity. Both pathogenicity and plasticity are tightly linked to IL-23 signaling. Here, we show that the protein tyrosine kinase Tec is highly induced in Th17 cells. Th17 differentiation was enhanced at low interleukin-6 (IL-6) concentrations in absence of Tec, which correlates with increased STAT3 phosphorylation and higher Il23r expression. Therefore, we uncovered a function for Tec in the IL-6 sensing via STAT3 by CD4+ T cells, defining Tec as a fine-tuning negative regulator of Th17 differentiation. Subsequently, by using the IL-17A fate mapping mouse combined with in vivo adoptive transfer models, we demonstrated that Tec not only restrained effector Th17 differentiation but also pathogenicity and plasticity in a T-cell intrinsic manner. Our data further suggest that Tec regulates inflammatory Th17-driven immune responses directly impacting disease severity in a T-cell-driven colitis model. Notably, consistent with the in vitro findings, elevated levels of the IL-23 receptor (IL-23R) were observed on intestinal pre- and postconversion Th17 cells isolated from diseased Tec−/− mice subjected to adoptive transfer colitis, highlighting a fundamental role of Tec in restraining IL-23R expression, likely via the IL-6-STAT3 signaling axis. Taken together, these findings identify Tec as a negative regulator of Th17 differentiation, pathogenicity, and plasticity, contributing to the mechanisms which help T cells to orchestrate optimal immune protection and to restrain immunopathology.

Role for granulocyte colony–stimulating factor in the generation of human T regulatory type 1 cells

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2562-2571 ◽  
Author(s):  
Sergio Rutella ◽  
Luca Pierelli ◽  
Giuseppina Bonanno ◽  
Simona Sica ◽  
Franco Ameglio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cell Contact ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Tgf Β1

Granulocyte colony–stimulating factor (G-CSF) may affect T-cell homeostasis by multiple mechanisms, inducing polarization of cytokine secretion, inhibition of T-cell proliferation, and enhancement of T-cell apoptosis. We analyzed the production of interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) by T cells from healthy volunteer donors treated with recombinant human G-CSF. Highly purified CD4+ T cells obtained before and after G-CSF administration (pre-G and post-G, respectively) were activated using the allogeneic mixed leukocyte reaction. Post-G CD4+T cells produced high levels of IL-10 but undetectable levels of IL-2 and IL-4, whereas the level of TGF-β1 release was comparable to that of pre-G CD4+ T cells. Notably, post-G CD4+ T cells proliferated poorly in response to alloantigens and to recall antigens and suppressed the proliferation of autologous CD4+ T cells in a cell contact–independent and an antigen-nonspecific manner. TGF-β1 and IL-10 were not dispensable for post-G CD4+ T cells to mediate suppression, as shown by neutralization studies. Compared with pre-G CD4+ T cells, alloantigen-activated post-G CD4+ T cells preferentially expressed markers associated with memory T cells, in conjunction with reduced levels of CD28 and CD62L. Collectively, these data demonstrate that CD4+ T cells exposed to G-CSF in vivo acquire the properties of T regulatory (Tr) cells once triggered in vitro through the T-cell receptor, including a peculiar cytokine production profile (IL-10++TGF-β1+IL-2low/−IL-4low/−), an intrinsic low proliferative capacity, and a contact-independent suppression of antigen-driven proliferation. Tr cells generated ex vivo after exposure to G-CSF might be clinically relevant for transplantation medicine and for the treatment of human immune-mediated diseases.

Smif (Smad4 Interacting Factor) Is a Negative Regulator of T Cell Activation and Autoimmunity In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 712-712 ◽  
Author(s):  
Wibke Leibig ◽  
Sebastian Kuhn ◽  
Thomas Patzelt ◽  
Claudia Mugler ◽  
Bai Ren-Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Negative Regulator ◽  
Exon 2 ◽  
Deficient Mice

Abstract Abstract 712 Transforming growth factor β (TGFβ) plays a critical role in regulating cellular processes like proliferation, extracellular matrix production, vasculogenesis and angiogenesis as well as immunomodulation. TGFβ is a pluripotent cytokine with a pronounced immunosuppressive effect by controlling proliferation, differentiation and activation of immune cells. TGFβ binding to its receptor leads to the phosphorylation of R-Smads. R-Smads again form a heteromeric complex with the cytosolic common Smad4. This Smad complex, together with additional cofactors, translocate into the nucleus, where they control the transcription of TGFβ target genes. Smif was originally identified in our lab as an interaction partner of Smad4. Functional analysis revealed a stimulatory effect in regulating TGFβ-dependent genes like the early target gene JunB. After TGFβ stimulation, Smif tranlocates, together with Smad4, into the nucleus, where Smif acts as a coactivator. To investigate the role of Smif in mammals, we generated a Smif knockout mouse. To this end exon 2 of Smif was replaced by GFP and an inverted neomycin selection cassette. Smif-deficient mice were viable but exhibit a shortened life span. On the average, these mice die at 12 month of age due to multifocal inflammatory disease. Overall pathological analysis of diseased mice revealed extensive lymphocytic infiltrates in multiple organs. Moreover, Smif-deficiency caused immune complex induced glomerulonephritis associated with proteinuria. In line with these findings, autoantibodies could be detected in the serum of Smif knockout mice. Interestingly, we identified T cells and not B-cells as the important target in Smif-deficient mice. T cells lacking Smif were spontaneously activated. In addition, TGFβ was not able to block T cell proliferation of CD4+ cells in vitro, whereas B cells isolated from Smif knockout spleens behave as wildtype. Transcription of TGFβ responsive reporter constructs was greatly reduced in Smif knockout Mefs and could be rescued by the reexpression of functional Smif. Taken all together, the observed autoimmune phenotype found in Smif-deficient mice is at least partially caused by overactivated T cells due to downregulation of the inhibitory TGFβ pathway. Disclosures: No relevant conflicts of interest to declare.

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