scholarly journals Proteoglycan Aggrecan Conducting T Cell Activation and Apoptosis in a Murine Model of Rheumatoid Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
A. Hanyecz ◽  
K. Olasz ◽  
O. Tarjanyi ◽  
P. Nemeth ◽  
K. Mikecz ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Systemic Autoimmune Disease ◽  
T Cell Epitopes ◽  
T Cell Apoptosis ◽  
Autoreactive T Cell

Rheumatoid arthritis (RA) is a systemic autoimmune disease and its targeting of the joints indicates the presence of a candidate autoantigen(s) in synovial joints. Patients with RA show immune responses in their peripheral blood to proteoglycan (PG) aggrecan. One of the most relevant animal models of RA appears to be proteoglycan-induced arthritis (PGIA), and CD4+T cells seem to play a crucial role in the initiation of the disease. In this review, the role of various T cell epitopes of aggrecan in the induction of autoreactive T cell activation and arthritis is discussed. We pay special attention to two critically important arthritogenic epitopes, 5/4E8 and P135H, found in the G1 and G3 domains of PG aggrecan, respectively, in the induction of autoimmune arthritis. Finally, results obtained with the recently developed PG-specific TCR transgenic mice system showed that altered T cell apoptosis, the balance of activation, and apoptosis of autoreactive T cells are critical factors in the development of autoimmunity.

scholarly journals T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia

2019 ◽  
Vol 17 (10) ◽  
pp. 1042-1052 ◽  
Author(s):  
Simo Xia ◽  
Xiang Liu ◽  
Xuetao Cao ◽  
Sheng Xu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Aplastic Anemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Autoreactive T Cell

Abstract The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.

T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease By Regulating Hematopoietic Antigen Presenting Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 846-846
Author(s):  
Jianing Fu ◽  
Yongxia Wu ◽  
Hung Nguyen ◽  
Jessica Lauren Heinrichs ◽  
Steven Schutt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Apoptosis ◽  
Cell Activation ◽  
T Cell Apoptosis ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Antigen Presenting

Abstract Graft-versus-host disease (GVHD) remains to be a major obstacle for the efficacy and continuing success of allogeneic hematopoietic stem cell transplantation in the treatment of various malignant and non-malignant diseases. Activation of antigen presenting cells (APCs), both host and donor origin, plays a crucial role in priming alloreactive donor T cells to induce and intensify acute GVHD (aGVHD). Beyond its critical effects on T cells, the T-box transcription factor T-bet also regulates activity of APCs, including dendritic cells (DCs) and B cells. However, the effect and mechanism of T-bet in regulating APCs in the development of aGVHD has not been investigated. To evaluate the role of T-bet in modulating APC function and aGVHD development, we compared the severity of aGVHD in WT versus T-bet-/- recipients using several well-defined, clinically relevant murine models of allogeneic bone marrow transplantation (allo-BMT). We observed that T-bet-/- recipients developed much milder aGVHD than their WT counterparts, reflected by significantly higher rate of survival, lower clinical scores, and better donor BM-derived B- and T-cell reconstitution. In T-bet-/- recipients, donor T cells significantly reduced IFN-γ production, proliferation and migration, and caused less damage in aGVHD target organs, such as liver and gut. By using various BM chimeras as the recipients, we further observed that T-bet expressed on recipient hematopoietic APCs was primarily responsible for donor T-cell response and pathogenicity in causing aGVHD. Additionally, we evaluated the role of T-bet in donor APCs by transplanting WT or T-bet-/- BM together with WT T cells into lethally irradiated allogeneic recipients. We observed that recipients of T-bet-/- BM developed attenuated aGVHD compared with those of WT BM, suggesting that T-bet also contributes to the function of donor APCs in the induction of GVHD. Given DCs are the most potent hematopoietic APCs, we subsequently focused on recipient DCs. DCs in T-bet-/- recipient produced less IFN-γ, expressed higher levels of Trail, but not FasL or TNF, to induce significantly higher levels of apoptosis on donor T cells prior to their massive proliferation. To test whether Trail/DR5 interaction is responsible for the induction of donor T cell apoptosis and subsequent reduction of aGVHD in T-bet-/- recipients, we compared the ability of WT or DR5-/- T cells in inducing aGVHD in WT versus T-bet-/- recipients after allo-BMT. While WT T cells induced severe aGVHD in WT recipients, they failed to do in T-bet-/- recipients. In contrast, DR5-/- donor T cells were capable to induce severe aGVHD in the recipients regardless of T-bet expression. These data suggests that Trail/DR5 interaction is a major signaling pathway responsible for donor T-cell apoptosis induced by T-bet-/- APCs, through which alleviates the development of aGVHD. In conclusion, we demonstrate that T-bet up-regulates IFN-γ production and down-regulates Trail expression on recipient DCs, which promotes donor T-cell activation and mitigates T-cell apoptosis, respectively. Thus, T-bet plays a critical role in the development of aGVHD by regulating the activity of hematopoietic APCs, particularly DCs. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of aGVHD through regulating T-cell activation and differentiation as well as APC functions. Disclosures No relevant conflicts of interest to declare.

scholarly journals AB0151 PRELIMINARY RESULTS SHOW AN INCREASED EXPRESSION OF COINHIBITORY RECEPTORS IN SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1376.2-1376
Author(s):  
M. Aspari ◽  
S. R. Greisen ◽  
M. Hvid ◽  
B. Deleuran ◽  
D. Abraham
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Systemic Sclerosis ◽  
T Cell ◽  
Healthy Volunteers ◽  
T Cell Activation ◽  
Cell Activation ◽  
Programmed Death ◽  
Programmed Death 1

Background:Recent studies suggest dysregulation in T cell activation in systemic sclerosis (SSc). Co-inhibitory-receptors (Co-IRs) such as TIM-3, PD-1 and LAG-3 play a crucial role in controlling excessive T cell activation and in maintaining immune homeostasis. Engagement of these receptors by their ligand’s limits cytokine production in response to TCR or activating NK receptor stimulation and hence limit tissue damage from excessive immune activation. However, chronically increased expression of multiple Co-IRs is a hallmark of immune exhaustion. We evaluate the role of these soluble Co-IRs in diffuse SSc (dcSSc).Objectives:Establish the role of CiR and their ligands in diffuse systemic sclerosis.Understand how immune regulatory mechanisms influence the development of fibrosis.Provide a better understanding of the disease and fibrosis in general.Methods:PBMC’s(Peripheral blood mononuclear cells) and dermal fibroblasts from SSc patients were isolated and investigated for markers of T cell inhibition. These cells were analysed using flow cytometry in a 10 colour panel. Cells were stained for PD1, TIM3, TIGIT, LAG3, CD3, CD8, CD4 and CD19 along with a Live/dead marker. Co-cultures of fibroblasts and PBMCs will be setup, and treated with various drugs that act on the Co-IRs.Results:The proportion of CD4+ T cells expressing PD1 were markedly increased in SSc patients compared to healthy volunteers and Rheumatoid Arthritis patients.There was increased expression of both TIGIT and TIM3 in the CD4+ T cells. (Figure 1)Similarly, the co-expression of these receptors on the CD4+ T cell population was elevated compared to healthy volunteers. (figure 2)Conclusion:Soluble co-inhibitors are differentially expressed in early dcSSc compared to healthy volunteers and other autoimmune diseases. Our preliminary data indicates that these co inhibitors could play an important role in unravelling the pathogenesis of systemic sclerosis. Inhibition or activation of these receptors through different treatment modalities can be utilized as a novel patient centric treatment strategy.References:[1]Fukasawa, T., Yoshizaki, A., Ebata, S., Nakamura, K., Saigusa, R., Miura, S., … Sato, S. (2017). Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis.Arthritis & Rheumatology,69(9), 1879–1890.[2]Greisen S, Rasmussen T, Stengaard-Pedersen K, Hetland M, Hørslev-Petersen K, Hvid M, et al. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand J Rheumatol 2014; 43:101-8.[3]de Paoli, F., Nielsen, B., Rasmussen, F., Deleuran, B., & Søndergaard, K. (2014). Abatacept induces clinical improvement in patients with severe systemic sclerosis.Scandinavian Journal of Rheumatology,43(4), 342–345.[4]Kwon, B. (2010). Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease.Experimental and Molecular Medicine. Nature Publishing Group.Acknowledgments:FOREUM: Foundation of Research in RheumatologyDisclosure of Interests:None declared

scholarly journals Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

scholarly journals HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

2019 ◽  
Vol 16 (4) ◽  
pp. 302-314
Author(s):  
Chinnambedu Ravichandran Swathirajan ◽  
Ramachandran Vignesh ◽  
Greer Waldrop ◽  
Uma Shanmugasundaram ◽  
Pannerselvam Nandagopal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Activation Rates ◽  
Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

scholarly journals Role of T-cell activation in salt-sensitive hypertension

2019 ◽  
Vol 316 (6) ◽  
pp. H1345-H1353 ◽  
Author(s):  
Jiafa Ren ◽  
Steven D. Crowley
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
T Subsets ◽  
Underlying Mechanisms ◽  
Salt Sensitive Hypertension

The contributions of T lymphocytes to the pathogenesis of salt-sensitive hypertension has been well established. Under hypertensive stimuli, naive T cells develop into different subsets, including Th1, Th2, Th17, Treg, and cytotoxic CD8+ T cells, depending on the surrounding microenviroment in organs. Distinct subsets of T cells may play totally different roles in tissue damage and hypertension. The underlying mechanisms by which hypertensive stimuli activate naive T cells involve many events and different organs, such as neoantigen presentation by dendritic cells, high salt concentration, and the milieu of oxidative stress in the kidney and vasculature. Infiltrating and activated T subsets in injured organs, in turn, exert considerable impacts on tissue dysfunction, including sodium retention in the kidney, vascular stiffness, and remodeling in the vasculature. Therefore, a thorough knowledge of T-cell actions in hypertension may provide novel insights into the development of new therapeutic strategies for patients with hypertension.

scholarly journals Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

2020 ◽  
Vol 21 (17) ◽  
pp. 6118 ◽  
Author(s):  
Marianna Szczypka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Splice Variants ◽  
Cell Activity ◽  
Cell Functions ◽  
Simultaneous Inhibition ◽  
And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

scholarly journals TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway

2019 ◽  
Vol 12 (4) ◽  
pp. 980-989 ◽  
Author(s):  
I. T. Chyuan ◽  
H. F. Tsai ◽  
C. S. Wu ◽  
P. N. Hsu
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Bowel Disease ◽  
Cell Activation ◽  
Gut Inflammation ◽  
Inflammatory Bowel ◽  
Colitis Model

AbstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

CD4+ T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis

2020 ◽  
Vol 5 (54) ◽  
pp. eabc6373
Author(s):  
Qing Zhao ◽  
Lennard W. Duck ◽  
Fengyuan Huang ◽  
Katie L. Alexander ◽  
Craig L. Maynard ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Formation ◽  
Metabolic Inhibition ◽  
T Cell Epitopes ◽  
Specific Memory

Microbiota-reactive CD4+ T memory (TM) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4+ T effector (TE) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike TE cells, TM cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4+ T cell–driven colitis. Microbiota-specific CD4+ T cells, especially the pathogenic TE subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific TM cell formation upon initial antigen encounter, and ablate existing TM cells upon reactivation in mice, leading to an altered transcriptome in the remaining CD4+ T cells after ablation. Microbiota flagellin–specific CD4+ T cells from patients with Crohn’s disease were ablated in a similar manner after CAMCI in vitro, with half of the antigen-specific T cells undergoing cell death. These results indicate that parenteral activation of microbiota-specific CD4+ T cells with concomitant metabolic inhibition is an effective way to ablate pathogenic CD4+ TM cells and to induce T regulatory (Treg) cells that provide antigen-specific and bystander suppression, supporting a potential immunotherapy to prevent or ameliorate IBD.

scholarly journals Akt Fine-tunes NF-κB-dependent Gene Expression during T Cell Activation

2011 ◽  
Vol 286 (41) ◽  
pp. 36076-36085 ◽  
Author(s):  
Jing Cheng ◽  
Binh Phong ◽  
David C. Wilson ◽  
Raphael Hirsch ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gene Profiling ◽  
Leukocyte Activation ◽  
Mrna Transcription ◽  
Tnf Α ◽  
Fine Tune

Activation of the NF-κB signaling pathway is critical for leukocyte activation and development. Although previous studies suggested a role for the Akt kinase in coupling the T cell antigen receptor and CD28 to NF-κB activation in T cells, the nature of the role of Akt in this pathway is still unclear. Using a targeted gene profiling approach, we found that a subset of NF-κB-dependent genes required Akt for optimal up-regulation during T cell activation. The selective effects of Akt were manifest at the level of mRNA transcription and p65/RelA binding to upstream promoters and appear to be due to altered formation of the Carma1-Bcl10 complex. The proinflammatory cytokine TNF-α was found to be particularly sensitive to Akt inhibition or knockdown, including in primary human blood T cells and a murine model of rheumatoid arthritis. Our findings are consistent with a hierarchy in the expression of NF-κB-dependent genes, controlled by the strength and/or duration of NF-κB signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-κB pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.

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