scholarly journals CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent manner

2008 ◽  
Vol 205 (9) ◽  
pp. 1975-1981 ◽  
Author(s):  
John Andersson ◽  
Dat Q. Tran ◽  
Marko Pesu ◽  
Todd S. Davidson ◽  
Heather Ramsey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
De Novo ◽  
Cell Contact ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Independent Manner

CD4+FoxP3+ regulatory T (T reg) cells comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. The molecular mechanism(s) by which T reg cells mediate their suppressive effects remains poorly understood. One molecule that has been extensively studied in T reg cell suppression is transforming growth factor (TGF)-β, but its importance remains controversial. We found that TGF-β complexed to latency-associated peptide (LAP) is expressed on the cell surface of activated but not resting T reg cells. T reg cell LAP–TGF-β plays an important role in the suppression of the proliferation of activated T cells, but it is not required for the suppression of naive T cell activation. More importantly, T reg cell–derived TGF-β could generate de novo CD4+FoxP3+ T cells in vitro from naive precursors in a cell contact–dependent, antigen-presenting cell–independent and αV integrin–independent manner. The newly induced CD4+FoxP3+ T cells are suppressive both in vitro and in vivo. Transfer of activated antigen-specific T reg cells with naive antigen-specific responder T cells to normal recipients, followed by immunization, also results in induction of FoxP3 expression in the responder cells. T reg cell–mediated generation of functional CD4+FoxP3+ cells via this TGF-β–dependent pathway may represent a major mechanism as to how T reg cells maintain tolerance and expand their suppressive abilities.

scholarly journals Mesenchymal Stromal Cells Rapidly Suppress TCR Signaling-Mediated Cytokine Transcription in Activated T Cells Through the ICAM-1/CD43 Interaction

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuwei Zheng ◽  
Ke Huang ◽  
Wenjie Xia ◽  
Jiahao Shi ◽  
Qiuli Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Diseases ◽  
Cell Contact ◽  
Dependent Manner ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Cell Cell

Cell-cell contact participates in the process of mesenchymal stromal cell (MSC)-mediated T cell modulation and thus contributes to MSC-based therapies for various inflammatory diseases, especially T cell-mediated diseases. However, the mechanisms underlying the adhesion interactions between MSCs and T cells are still poorly understood. In this study, we explored the interaction between MSCs and T cells and found that activated T cells could rapidly adhere to MSCs, leading to significant reduction of TNF-α and IFN-γ mRNA expression. Furthermore, TCR-proximal signaling in activated T cells was also dramatically suppressed in the MSC co-culture, resulting in weakened Ca2+ signaling. MSCs rapidly suppressed TCR signaling and its downstream signaling in a cell-cell contact-dependent manner, partially through the ICAM-1/CD43 adhesion interaction. Blockade of either ICAM-1 on MSCs or CD43 on T cells significantly reversed this rapid suppression of proinflammatory cytokine expression in T cells. Mechanistically, MSC-derived ICAM-1 likely disrupts CD43-mediated TCR microcluster formation to limit T cell activation. Taken together, our results reveal a fast mechanism of activated T cell inhibition by MSCs, which provides new clues to unravel the MSC-mediated immunoregulatory mechanism for aGVHD and other severe acute T cell-related diseases.

T cell-T cell activation in multiple sclerosis

1997 ◽  
Vol 3 (4) ◽  
pp. 238-242 ◽  
Author(s):  
JW Lindsey ◽  
RH Kerman ◽  
JS Wolinsky
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Activated T Cells ◽  
In Vitro Proliferation

Activated T cells are able to stimulate proliferation in resting T cells through an antigen non-specific mechanism. The in vivo usefulness of this T cell-T cell activation is unclear, but it may serve to amplify immune responses. T cell-T cell activation could be involved in the well-documented occurrence of multiple sclerosis (MS) exacerbations following viral infections. Excessive activation via this pathway could also be a factor in the etiology of MS. We tested the hypothesis that excessive T cell-T cell activation occurs in MS patients using in vitro proliferation assays comparing T cells from MS patients to T cells from controls. When tested as responder cells, T cells from MS patients proliferated slightly less after stimulation with previously activated cells than T cells from controls. When tested as stimulator cells, activated cells from MS patients stimulated slightly more non-specific proliferation than activated cells from controls. Neither of these differences were statistically significant We conclude that T cell proliferation in response to activated T cells is similar in MS and controls.

Effects of Ca-Containing Phosphate Glasses on T Lymphocytes In Vitro

2005 ◽  
Vol 284-286 ◽  
pp. 597-602 ◽  
Author(s):  
A. Kesisoglou ◽  
Jonathan C. Knowles ◽  
I. Olsen
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Dna Synthesis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Suppressor Cells ◽  
Phosphate Glasses ◽  
Activated T Cells

Calcium phosphate-based glasses (PG) are of interest as both scaffold and delivery materials for tissue rebuilding because of their chemical similarity to bone. Since it is essential that these materials exhibit local and systemic biocompatibility and do not adversely affect host tissues, the present study was undertaken to examine the effects of PG containing different amounts of Ca on human T lymphocytes in vitro. This was carried out by measuring the effects of extracts of the PG on the direct and mitogen-induced activation of T cells from human peripheral blood, as well as assessing CD4 and CD8, surface antigens which define T-helper and T-suppressor cells, respectively. The results showed that DNA synthesis by resting T lymphocytes was unaffected by all the PG. However, extracts of the PG containing 24 mol% of Ca caused a very marked inhibition of mitogen-induced T cell activation. This PG also reduced both the resting CD4+ and CD8+ T cells, as well as activated CD8+ cells. In contrast, high Ca-PG significantly augmented DNA synthesis by mitogen-activated T cells. These experiments show that PG containing differing levels of Ca can have pronounced and differential effects on the activation and function of T lymphocytes in vitro.

scholarly journals Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules

2021 ◽  
Vol 12 ◽  
Author(s):  
Marlies J. W. Peeters ◽  
Pia Aehnlich ◽  
Adriano Pizzella ◽  
Kasper Mølgaard ◽  
Tina Seremet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Oxidative Phosphorylation ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Activated T Cells ◽  
Inhibition Of Proliferation ◽  
Effector Molecules ◽  
Pyrimidine Synthesis

T-cell activation upon antigen stimulation is essential for the continuation of the adaptive immune response. Impairment of mitochondrial oxidative phosphorylation is a well-known disruptor of T-cell activation. Dihydroorotate dehydrogenase (DHODH) is a component of the de novo synthesis of pyrimidines, the activity of which depends on functional oxidative phosphorylation. Under circumstances of an inhibited oxidative phosphorylation, DHODH becomes rate-limiting. Inhibition of DHODH is known to block clonal expansion and expression of effector molecules of activated T cells. However, this effect has been suggested to be caused by downstream impairment of oxidative phosphorylation rather than a lower rate of pyrimidine synthesis. In this study, we successfully inhibit the DHODH of T cells with no residual effect on oxidative phosphorylation and demonstrate a dose-dependent inhibition of proliferation of activated CD3+ T cells. This block is fully rescued when uridine is supplemented. Inhibition of DHODH does not alter expression of effector molecules but results in decreased intracellular levels of deoxypyrimidines without decreasing cell viability. Our results clearly demonstrate the DHODH and mitochondrial linked pyrimidine synthesis as an independent and important cytostatic regulator of activated T cells.

scholarly journals RIAM Interacts with the Hematopoietic-Specific Adaptor Protein Gads and Forms a LAT-Independent Node of Signal Integration That Regulates Activation of PLC-γ1

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4138-4138
Author(s):  
Kankana Bardhan ◽  
Nikolaos Patsoukis ◽  
Donna M Berry ◽  
Jane McGlade ◽  
Vassiliki A. Boussiotis
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Ph Domain ◽  
Activated T Cells ◽  
Independent Manner ◽  
C Terminus

Abstract TCR stimulation triggers the activation of protein tyrosine kinases resulting in phosphorylation of the adaptor protein LAT. SLP-76, interacts constitutively with PLC-γ1 and with the SH3 domain of Gads, which via its SH2 domain mediates inducible recruitment of SLP-76 and PLC-γ1 to LAT, upon T cell activation. PLC-γ1 hydrolyzes phosphatidylinositol-4, 5 bisphosphate [PI(4,5)P2], generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), second messengers responsible for mediating intracellular calcium release and activation of downstream signals. The adaptor protein RIAM constitutively interacts with PLC-γ1 and is required for PLC-γ1 activation. RIAM is a multidomain protein with a small N-terminus proline-rich region, two coiled-coiled regions, sequential Ras association (RA) and pleckstrin homology (PH) domains, and a large C-terminus proline-rich region, which interacts with PLC-γ1. The RA domain of RIAM has specificity for Rap1-GTP whereas the PH domain binds to the PLC-γ1 substrate PI(4,5)P2. The RA-PH domain region of RIAM functions as a single structural unit and mediates translocation of RIAM to the plasma membrane upon T cell activation. Previously, we determined that RIAM deficiency results in impaired activation of PLC-γ1 in spite of the formation of the PLC-γ1-SLP-76-LAT complex, suggesting perhaps somewhat paradoxically, that PLC-γ1-SLP-76-LAT signalosome is not sufficient to mediate distal signaling in the absence of RIAM. This observation indicated that RIAM mediates its effects at a level distal to SLP-76-LAT or through a signaling pathway parallel but distinct from SLP-76-Gads-LAT. Here we investigated whether RIAM forms a signalosome parallel to PLC-γ1-SLP-76-Gads and whether such pathway might be involved in the activation of PLC-γ1. Using primary T lymphocytes and Jurkat T cells stimulated via TCR/CD3 and CD28 we determined that RIAM constitutively interacted with Gads as determined by immunoprecipitation with RIAM-specific antibody followed by Gads immunoblot. To determine whether the interaction between RIAM and Gads was direct, we employed an in vitro protein association assay. Glutathione S-transferase (GST) and GST-fusion protein of Gads were coupled to glutathione-sepharose and incubated with [35S]methionine-labeled RIAM or luciferase, as negative control. Gads bound to [35S]methionine-labeled RIAM indicating that RIAM interacts directly with Gads. We further examined domain-specific interaction of RIAM with endogenous Gads using GST fusion proteins of RIAM. We determined a constitutive interaction between Gads and GST fusion proteins of full-length RIAM or C-terminus region of RIAM. Although a number of tyrosine phosphorylated proteins were associated with the RIAM-Gads complex upon T cell activation, LAT was not detected among the components of this complex as determined by immunoblot with anti-phosphotyrosine-specific or LAT-specific antibodies. Using a GST fusion protein of the RA-PH domain of RIAM we determined that, surprisingly, Gads displayed activation-dependent interaction with the RA-PH domain, which mediates the recruitment of RIAM to the plasma membrane upon T cell activation. Furthermore, in addition to Gads, SLP-76 and PLC-γ1 were recruited to the RA-PH domain of RIAM in activated T cells. To determine whether RIAM and Gads had a synergistic effect on IL-2 transcription, we performed luciferase-based reporter assays using a reporter construct driven by the entire IL-2 promoter or by NFAT binding sequences. We found that RIAM and Gads had a synergistic effect on IL-2 and on NFAT-mediated transcriptional activation, which depends on PLC-γ1. Thus, via its C-terminus region, RIAM directly and constitutively interacts with Gads. In addition, via its RA-PH domain, RIAM mediates an activation-dependent interaction with Gads and serves as a docking site recruiting the PLC-γ1-SLP-76-Gads complex to the plasma membrane in a LAT-independent manner. These findings indicate a crosstalk between RIAM and SLP-76 in the activation of PLC-γ1 and reveal a previously unidentified, alternative signaling pathway leading to Gads-SLP-76 recruitment to the plasma membrane of activated T cells in a LAT-independent manner. Disclosures No relevant conflicts of interest to declare.

scholarly journals THYMUS-DERIVED CELL (T CELL) ACTIVATION BY HETEROLOGOUS ANTIGENS AS A REPLACEMENT OF SPECIFIC IMMUNE T CELLS IN THE TRANSFER OF THE SECONDARY RESPONSE TO SHEEP ERYTHROCYTES

1972 ◽  
Vol 136 (4) ◽  
pp. 715-721 ◽  
Author(s):  
J. J. Mond ◽  
T. Takahashi ◽  
G. J. Thorbecke
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Keyhole Limpet Hemocyanin ◽  
Secondary Response ◽  
Activated T Cells ◽  
Sheep Erythrocytes ◽  
Cell Responses ◽  
Heterologous Antigens

Spleen cells from LAF1 mice hyperimmune to sheep erythrocytes (SE) lost their ability to transfer a secondary response to irradiated recipients after incubation with anti-θ and rabbit complement in vitro. Small numbers of specific immune cells even when taken 3 days after a primary SE injection reconstituted the direct and indirect plaque-forming cell responses. Larger numbers of cells sensitized to B. abortus (or keyhole limpet hemocyanin), and given together with the corresponding antigen, also partially reconstituted the ability to respond to SE. This property was mediated by θ-bearing cells and was interpreted as due to a nonspecific humoral factor liberated by specifically activated T cells and acting on B cell proliferation or maturation.

Phenotypic and Functional Characterization Of a Novel Immature Hematopoietic Myeloid Suppressive Progenitor Cells Mobilized By G-CSF. Application To Gvhd Treatment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4476-4476
Author(s):  
Marie T Rubio ◽  
Maud D'Aveni ◽  
Tereza Coman ◽  
Julien Rossignol ◽  
Julie Bruneau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Acute Gvhd ◽  
Activated T Cells ◽  
Stem Cell Graft ◽  
Alloreactive T Cell

Background Myeloid derived suppressive cells (MDSCs) represent a heterogeneous population of cells endowed with immunosuppressive properties. They have been first described in the tumor microenvironment. Some mature MDSCs either induced by GM-CSF and IL-13 (Highfill et al., Blood 2010) or mobilized by G-CSF (Joo et al., Immunology 2009) have been reported to control experimental GVHD by inhibiting alloreactive T cell proliferation. We describe here the existence in mice and humans of a not yet characterized population of GCSF-mobilized hematopoïetic cells with phenotypic characteristics of immature MDSCs (called therefore pro-MDSCs) that can inhibit GVHD by a distinct mechanism than those described with classical mature MDSCs. Methods In the C57BL6 mouse and human, G-CSF mobilized MDSCs were collected and analyzed in the spleen and PBSC using several antibodies directed against various markers of maturity, lineage specific antigens and chemokine receptors. Depending on the expression of maturity antigens various population were sorted. In vitro, functions of sorted MDSC were analyzed by co-cultures with T cells activated either by anti-CD3 and CD28 mAbs or allogeneic dendritic cells. In vivo, the effect of various population of MDSCs on GVHD was assessed either by the transfer of murine C57BL6 (H-2b) cells (2x106 splenic T cells + 5x106 T depleted bone marrow cells +/- 0.5x106 MDSC subtypes) into lethally irradiated BALB/c (H-2d) recipients or by injecting 2x105 human pro-MDSCs with 2.5x106 human PBMC into 2 Gy irradiated Nod/SCID/gammac-/- mice. In 19 allografted patients, proportions of MDSC subpopulations contained in the peripheral stem cell graft were correlated to the occurrence of acute GVHD and to the post-transplant peripheral blood levels of conventional proliferating T cells and CD4+ CD25+ CD127low reguatory T cells (T regs). Results In the G-CSF mobilized cells, immature Lin- Sca1high cKithigh CD34+ CX3CR1+ CD16/32+ CD11b+ Ly6C+ and Lin- CD34+ HLA-DR- CD33high CD11blow CD14+ cell populations were identified in mice spleen and human PBSC, respectively. Because the pattern of maturity antigen expression, these populations were named pro-MDSCs. The mature MDSC counterparts shared the same differentiation phenotype without the markers of maturity. In vitro, both murine and human pro-MDSCs, but not the corresponding mature MDSCs, could inhibit the proliferation and induced the apoptosis of activated T cells (p<0,001). The inhibition of T cell activation by pro-MDSCs required IFN-gamma produced by activated T-cells and the production of NO by pro-MDSCs in response to IFN-gamma. NO suppressed T-cell functions through impaired responses to IL2 and induction of apoptosis. In vivo, in the C57BL6 to BALB/c GVHD model, the administration of murine pro-MDSCs significantly reduced the development of clinical and histological GVHD signs as compared to allografted mice without pro-MDSCs or with GCSF-mobilized mature MDSCs (p=0,03). Murine pro-MDSCs could migrate to site of allo-priming and induced the apoptosis of allogeneic T cells when compared to mice allografted without pro-MDSCs (p<0,01). In mice that had received pro-MDSCs, we observed that apoptotic T cells could be engulfed by phagocytes and that those phagocytes produced high levels of cytokines (IL-10, TGF-beta), which was associated with increased induced CD4+CD25+Foxp3+ T regs leading to the induction of tolerance. These observations were not seen in mice allografted without pro-MDSCs (p<0,05). Human pro-MDSCs could protect all xeno-grafted Nod/SCID/gamma c-/- mice from GVHD mortality as compared to 100% GVHD lethality in controlled xeno-grafted mice without pro-MDSCs (p<0,001). Allografted patients having received a stem cell graft containing levels of Pro-MDSCs >10% of the CD34+ fraction had a significantly reduced risk of developing grade II-IV acute GVHD (p= 0,04) and reduced numbers of proliferating conventional T cells but higher numbers of T regs in the peripheral blood on days 15 and 30 post-HSCT (p<0.05). No correlation between the occurrence of acute GVHD and the proportions of mature MDSCs contained in the graft was observed. Conclusion We have characterized a new homogeneous population of G-CSF mobilized immature MDSCs, which has been named pro-MDSC that can regulate alloreactive T cell activation in vitro and in vivo by inducing tolerance with potential therapeutic application in allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

2002 ◽  
Vol 196 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Ciriaco A. Piccirillo ◽  
John J. Letterio ◽  
Angela M. Thornton ◽  
Rebecca S. McHugh ◽  
Mizuko Mamura ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Transforming Growth Factor ◽  
Cell Contact ◽  
Suppressor Function ◽  
Tgf Β1

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25−T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact–dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti–TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3−/− or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1–induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1−/− mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1.

Upregulation of TRAIL expression on human T lymphocytes by interferon b and glatiramer acetate

2005 ◽  
Vol 11 (6) ◽  
pp. 652-657 ◽  
Author(s):  
N Arbour ◽  
E Rastikerdar ◽  
E McCrea ◽  
Y Lapierre ◽  
J Dörr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Glatiramer Acetate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Effects ◽  
Activated T Cells ◽  
Trail Expression

We measured the in vivo and in vitro effects of interferon (IFN)b and glatiramer acetate (GA) on the expression of the regulatory molecule, tumor necrosis factor related apoptosis inducing ligand (TRAIL), in patients with multiple sclerosis (MS). We confirmed the prior observation that TRAIL is enhanced on anti-CD3 activated T cells by the in vitro addition of IFNβ. T cells from IFNβ-treated patients stimulated with anti-CD3 only, had higher levels of TRAIL than untreated patients, suggesting that in vivo IFNβ exposure has an effect on TRAIL expression in association with T cell activation. In vitro IFNβ-induced TRAIL upregulation on anti-CD3 or phytohemagglutinin-activated T cells was comparable for IFNβ-treated and non-treated MS patients and controls, indicating that IFN receptors were neither saturated nor down-regulated by current IFNβ therapy. Although GAin vivo orin vitro did not induce TRAIL, the IFNβ-GA combination in vitro enhanced TRAIL expression to higher levels than IFNβ alone on CD4+ T cells obtained from MS patients, regardless of GA treatment status, and healthy donors, and on GA reactive T cell lines derived from GA-treated patients or controls. Whether any observed therapeutic effects of GA/IFNβ combination therapy will correlate with TRAIL expression and function remains to be determined.

scholarly journals Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Yan ◽  
Weiwei Chen ◽  
Hua Song ◽  
Xianming Long ◽  
Zhuoya Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I ◽  
Dependent Manner ◽  
Dsdna Antibody

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

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