scholarly journals A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice

2005 ◽  
Vol 201 (6) ◽  
pp. 949-960 ◽  
Author(s):  
Hiroyuki Yoshitomi ◽  
Noriko Sakaguchi ◽  
Katsuya Kobayashi ◽  
Gordon D. Brown ◽  
Tomoyuki Tagami ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Arthritis ◽  
Autoimmune Arthritis ◽  
Independent Manner ◽  
Polycytidylic Acid ◽  
Clean Environment ◽  
Microbial Environment ◽  
Genetic And Environmental Factors ◽  
Mild Arthritis

A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal β-glucan, or purified β-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice. Blockade of Dectin-1, a major β-glucan receptor, can prevent SKG arthritis triggered by β-glucans, which strongly activate dendritic cells in vitro in a Dectin-1–dependent but Toll-like receptor-independent manner. Furthermore, antibiotic treatment against fungi can prevent SKG arthritis in an arthritis-prone microbial environment. Multiple injections of polyinosinic-polycytidylic acid double-stranded RNA also elicit mild arthritis in SKG mice. Thus, specific microbes, including fungi and viruses, may evoke autoimmune arthritis such as rheumatoid arthritis by stimulating innate immunity in individuals who harbor potentially arthritogenic autoimmune T cells as a result of genetic anomalies or variations.

PIR-B expressing CD8+ T cells exhibit features of Tc1 and Tc17 in SKG mice

Rheumatology ◽  
2019 ◽  
Vol 58 (12) ◽  
pp. 2325-2329 ◽  
Author(s):  
Kathrin Rothe ◽  
Dagmar Quandt ◽  
Gabriele Köhler ◽  
Simon Jasinski-Bergner ◽  
Barbara Seliger ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Peripheral Tolerance ◽  
Autoimmune Arthritis ◽  
Specific Pathogen ◽  
Inflammatory Phenotype

Abstract Objective In autoimmune arthritis, TCR signalling is attenuated by peripheral tolerance mechanisms. We have described previously a population of inhibitory receptor LIR-1 expressing autoreactive CD8+ T cells in rheumatoid arthritis. Here, we investigated the role of CD8+ T cells in murine autoimmune arthritis by analysing their expression of the mouse orthologue of LIR-1, PIR-B. Methods Frequencies of PIR-B+CD8+ T cells were determined in the SKG arthritis model. The phenotype of those cells was determined ex vivo by FACS and functionality was investigated by means of cytokine production and cytolytic potential upon activation in vitro. Results SKG mice, under non-SPF (specific pathogen-free) conditions with clinical symptoms of arthritis, were found to harbour significantly increased frequencies of PIR-B+CD8+ T cells. Those cells showed a pro-inflammatory phenotype with preferential production of IL-17 and IFN-γ. The frequency of those cells correlated inversely with the arthritis score, indicating that they might represent autoreactive, but functionally inhibited, CD8+ T cells. Conclusion PIR-B+CD8+ T cells from SKG mice show a cytotoxic and pro-inflammatory phenotype. Inhibition of CD8+ T cell autoreactivity by PIR-B/LIR-1 receptor signalling might be a counter-regulatory mechanism to curb autoreactivity and arthritis.

scholarly journals Thymic selection pathway regulates the effector function of CD4 T cells

2007 ◽  
Vol 204 (9) ◽  
pp. 2145-2157 ◽  
Author(s):  
Wei Li ◽  
M. Hanief Sofi ◽  
Norman Yeh ◽  
Sarita Sehra ◽  
Brian P. McCarthy ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Mrna Level ◽  
Cell Receptor ◽  
Effector Function ◽  
Thymic Selection ◽  
Th2 Cytokines ◽  
Independent Manner

Recently, a new developmental pathway for CD4 T cells that is mediated by major histocompatibility complex class II–positive thymocytes was identified (Choi, E.Y., K.C. Jung, H.J. Park, D.H. Chung, J.S. Song, S.D. Yang, E. Simpson, and S.H. Park. 2005. Immunity. 23:387–396; Li, W., M.G. Kim, T.S. Gourley, B.P. McCarthy, D.B. Sant'angelo, and C.H. Chang. 2005. Immunity. 23:375–386). We demonstrate that thymocyte-selected CD4 (T-CD4) T cells can rapidly produce interferon γ and interleukin (IL) 4 upon in vivo and in vitro T cell receptor stimulation. These T-CD4 T cells appear to be effector cells producing both T helper type 1 (Th1) and Th2 cytokines, and they maintain a potential to produce Th2 cytokines under Th1-skewing conditions in a signal transducer and activator of transcription 6–independent manner. The IL-4 mRNA level is high in CD4 single-positive thymocytes if they are selected on thymocytes, which is at least partly caused by enhanced histone acetylation of the IL-4 locus. However, mice that can generate T-CD4 T cells showed attenuated immune responses in an allergen-induced airway inflammation model, suggesting a protective role for T-CD4 T cells during an airway challenge. Our results imply that this thymic selection pathway plays an important role in determining the effector function of the resulting CD4 cells and in regulating immune response.

scholarly journals MyD88 Expression Is Required for Efficient Cross-Presentation of Viral Antigens from Infected Cells

2005 ◽  
Vol 79 (5) ◽  
pp. 2964-2972 ◽  
Author(s):  
Margaret Chen ◽  
Christina Barnfield ◽  
Tanja I. Näslund ◽  
Marina N. Fleeton ◽  
Peter Liljeström
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Independent Manner ◽  
Cross Presentation ◽  
Microbial Infections ◽  
Infected Cells ◽  
Strict Requirement ◽  
Lymphocyte Responses

ABSTRACT While virus-infected dendritic cells (DCs) in certain instances have the capacity to activate naïve T cells by direct priming, cross-priming by DCs via the uptake of antigens from infected cells has lately been recognized as another important pathway for the induction of antiviral immunity. During cross-priming, danger and stranger signals play important roles in modulating immune responses. Analogous to what has been shown for other microbial infections, virally infected cells may contain several pathogen-associated molecular patterns that are recognized by Toll-like receptors (TLRs). We analyzed whether the efficient presentation of antigens derived from infected cells requires the usage of MyD88, which is a common adaptor molecule used by all TLRs. For this study, we used murine DCs that were wild type or deficient in MyD88 expression and fibroblasts that were infected with an alphavirus replicon to answer this question. Our results show that when DCs are directly infected, they are able to activate antigen-specific CD8+ T cells in a MyD88-independent manner. In contrast, a strict requirement of MyD88 for cross-priming was observed when virally infected cells were used as a source of antigen in vitro and in vivo. This indicates that the effects of innate immunity stimulation via the MyD88 pathway control the efficiency of cross-presentation, but not direct presentation or DC maturation, and have important implications in the development of cytotoxic T lymphocyte responses against alphaviral replicon infections.

scholarly journals IL-27 confers a protumorigenic activity of regulatory T cells via CD39

2019 ◽  
Vol 116 (8) ◽  
pp. 3106-3111 ◽  
Author(s):  
Young-Jun Park ◽  
Heeju Ryu ◽  
Garam Choi ◽  
Byung-Seok Kim ◽  
Eun Sook Hwang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Antitumor Immunity ◽  
Suppressive Activity ◽  
Independent Manner ◽  
Bone Marrow Chimera ◽  
Cell Responses

Expression of ectonucleotidase CD39 contributes to the suppressive activity of Foxp3+ regulatory T cells (Tregs) by hydrolyzing immunogenic ATP into AMP. The molecular mechanism that drives CD39 expression on Tregs remains elusive. We found that tumor-infiltrating Tregs (Ti-Tregs) failed to up-regulate CD39 in mice lacking EBI3 subunit of IL-27 or IL-27Ra. Mixed bone marrow chimera and in vitro studies showed that IL-27 signaling in Tregs directly drives CD39 expression on Ti-Tregs in a STAT1-dependent, but STAT3- and T-bet–independent, manner. Tregs stimulated with IL-27 showed enhanced suppressive activities against CD8+ T cell responses in vitro. Moreover, IL-27Ra–deficient Tregs and STAT1-deficient Tregs were less efficient than WT Tregs in suppressing antitumor immunity in vivo. CD39 inhibition significantly abolished IL-27–induced suppressive activities of Tregs. Thus, IL-27 signaling in Tregs critically contributes to protumorigenic properties of Tregs via up-regulation of CD39.

A Novel Humanised ROR1 Bi-Specific T-Cell Engager Molecule for the Treatment of Chronic Lymphocytic Leukaemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3244-3244
Author(s):  
Satyen Harish Gohil ◽  
Micaela Harrasser ◽  
Solange R Paredes-Moscosso ◽  
Amit C Nathwani ◽  
Marco Della Peruta
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukaemia ◽  
Cell Lines ◽  
Lymphocytic Leukaemia ◽  
Orphan Receptor ◽  
Single Chain ◽  
Lymphoid Leukaemia ◽  
Independent Manner

Abstract Bispecific T-cell Engagers (BiTEs) are a promising immunotherapeutic approach, usually consisting of two single chain variable fragments (scFv) linked in tandem. One arm binds to tumour-associated antigens, whilst the other binds CD3 on T-cells, facilitating the formation of cytotoxic synapses leading to killing of tumour targets in a MHC and co-stimulatory molecule independent manner. Blinatumomab, the most advanced BiTE in clinic targets CD19 and has shown impressive results in patients with relapsed/refractory B cell acute lymphoid leukaemia but results in elimination of normal and malignant B lymphocytes. Receptor Tyrosine Kinase Like Orphan receptor is a surface antigen expressed on a range of haematological and solid malignancies, including Chronic Lymphocytic Leukaemia (CLL), Acute Lymphoblastic Leukaemia (ALL), and cancer stem cell-like cells (CSC). It is however expressed at low or undetectable levels in normal tissues making it an attractive target for immunotherapy approaches. We generated a panel of novel fully humanised ROR1 antibodies and selected an optimal scFv based on ROR1 binding to use in our BiTE format. Our ROR1 BiTE (ROR1xCD3), at low concentrations, was efficient inducing T-cell mediated cytotoxicity and consequent inflammatory cytokine secretion against a panel of haematopoietic cell lines with constitutive ROR1 expression in vitro. Importantly cytotoxicity was comparable to that seen with a control CD19 BITE. Moreover, ROR1xCD3 led to significant and selective cytotoxicity of primary CLL samples. We transitioned our in vitro studies to animal models and showed that our ROR1xCD3 is able to retard growth of established SKW cells engrafted in immunocompromised mice, as detected by bioluminescence imaging. Additionally ROR1xCD3 improved survival, with the ROR1xCD3 treated cohort showing improved median survival of 50 days compared to control mice of 18 days despite only receiving a single infusion of T-cells. In summary, we have developed a novel ROR1 BiTE able to target an array of haematopoietic malignancies. Our ROR1 BiTE induces T-cell cytotoxicity against ROR1 positive cell lines in vitro and in vivo as well as primary CLL cells and has the potential to be a beneficial therapeutic for CLL. Disclosures Gohil: UCL Business: Patents & Royalties: ROR1 based immunotherapies. Paredes-Moscosso:UCL Business: Patents & Royalties: ROR1 based immunotherapies. Nathwani:UCL Business: Patents & Royalties: ROR1 based Immunotherapies. Della Peruta:UCL Business: Patents & Royalties: ROR1 based immunotherapies.

Nitric oxide induces polarization of actin in encephalitogenic T cells and inhibits their in vitro transendothelial migration in a p70S6 kinase‐independent manner

2003 ◽  
Vol 17 (10) ◽  
pp. 1337-1339 ◽  
Author(s):  
Maria A. Staykova ◽  
Leise A. Berven ◽  
William B. Cowden ◽  
David O. Willenborg ◽  
Michael F. Crouch
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Transendothelial Migration ◽  
Independent Manner ◽  
P70s6 Kinase

scholarly journals Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1914
Author(s):  
Pepe M. Ekulu ◽  
Oyindamola C. Adebayo ◽  
Jean-Paul Decuypere ◽  
Linda Bellucci ◽  
Mohamed A. Elmonem ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Lines ◽  
Cell Model ◽  
Kidney Diseases ◽  
Poly I:C ◽  
Autophagic Flux ◽  
Independent Manner ◽  
Polycytidylic Acid ◽  
Functional Features

Apolipoprotein L1 (APOL1) high-risk genotypes (HRG), G1 and G2, increase the risk of various non-diabetic kidney diseases in the African population. To date, the precise mechanisms by which APOL1 risk variants induce injury on podocytes and other kidney cells remain unclear. Trying to unravel these mechanisms, most studies have used animal or cell models created by gene editing. We developed and characterised conditionally immortalised human podocyte cell lines derived from urine of a donor carrying APOL1 HRG G2/G2. Following induction of APOL1 expression by polyinosinic-polycytidylic acid (poly(I:C)), we assessed functional features of APOL1-induced podocyte dysfunction. As control, APOL1 wild type (G0/G0) podocyte cell line previously generated from a Caucasian donor was used. Upon exposure to poly(I:C), G2/G2 and G0/G0 podocytes upregulated APOL1 expression resulting in podocytes detachment, decreased cells viability and increased apoptosis rate in a genotype-independent manner. Nevertheless, G2/G2 podocyte cell lines exhibited altered features, including upregulation of CD2AP, alteration of cytoskeleton, reduction of autophagic flux and increased permeability in an in vitro model under continuous perfusion. The human APOL1 G2/G2 podocyte cell model is a useful tool for unravelling the mechanisms of APOL1-induced podocyte injury and the cellular functions of APOL1.

Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in “human immune system” Rag2-/-γc-/- mice

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 238-245 ◽  
Author(s):  
Nicolas Legrand ◽  
Tom Cupedo ◽  
Anja U. van Lent ◽  
Menno J. Ebeli ◽  
Kees Weijer ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Opportunistic Infections ◽  
Human Immune System ◽  
Independent Manner ◽  
Human T Cell ◽  
Human Immune

Efficient and quick reconstitution of T-cell compartments in lymphopenic patients is of great importance to prevent opportunistic infections, but remains difficult to achieve. Human T-cell proliferation in a T-cell-receptor (TCR)-independent manner is possible in vitro with superagonist anti-CD28 antibodies, and such molecules are therefore promising therapeutic tools. Here, we investigated the in vivo effects of superagonist anti-CD28 treatment on human developing and mature T cells, in the recently developed model of “human immune system” BALB/c Rag2-/-γc-/- mice. Our results show that superagonist anti-CD28 treatment transiently induces a 7-fold increase in thymocyte numbers and up to 18-fold accumulation of mature thymocytes. The increased thymic production lead to transient accumulation of mature T cells in the periphery at the peak of treatment effect (day 6). In addition, long-term peripheral T-cell depletion was induced. Furthermore, the concomitant selective expansion and accumulation of suppressive CD4+CD25+FoxP3+ T cells was induced in a transient manner. Superagonist anti-CD28 therapy could therefore be of clinical interest in humans, both for beneficial effect on thymic T-cell production as well as regulatory T-cell accumulation. (Blood. 2006;108:238-245)

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 Interleukin 4 (IL-4) or IL-7 Prevents the Death of Resting T Cells: Stat6 Is Probably Not Required for the Effect of IL-4

1997 ◽  
Vol 186 (2) ◽  
pp. 325-330 ◽  
Author(s):  
Anthony Vella ◽  
T. Kent Teague ◽  
James Ihle ◽  
John Kappler ◽  
Philippa Marrack
Keyword(s):  
Tissue Culture ◽  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Interleukin 4 ◽  
Active Process ◽  
Independent Manner ◽  
T Cell Survival ◽  
And Function

Although much is known about the activation, proliferation, and function of CD4+ T cells, little is known about how they survive as resting T cells in animals. Resting T cells have a half-life in animals of more than a week; however, when they are removed from animals and placed in tissue culture their half-life falls to ∼24 h. In this paper, we show that the survival of resting T cells in vitro is promoted by two cytokines, interleukins 4 and 7 (IL-4, IL-7). They may do this in part by maintaining levels of survival-promoting proteins such as Bcl-2 in the cells, because the levels of Bcl-2 and Bcl-Xl in resting T cells fall rapidly after the cells are isolated from animals, and are maintained by culture in IL-4. Because the IL-4 receptor is known to signal through the JAK1 and JAK3/Stat6 pathway, we tested whether Stat6 was required for IL-4– dependent T cell survival. Surprisingly, we found that IL-4 rescued T cells from apoptosis in what appeared to be a Stat6-independent manner. These results demonstrate that the survival of resting T cells is an active process that can be affected by signals delivered by cytokines and also suggest that the IL-4 receptor on resting T cells may use a novel signaling pathway to facilitate T cell viability.

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