Induction of costimulation of human CD4 T cells by tumor necrosis factor-related apoptosis-inducing ligand: Possible role in T cell activation in systemic lupus erythematosus

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.

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Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1605081113 ◽

2016 ◽

Vol 113 (33) ◽

pp. 9321-9326 ◽

Cited By ~ 16

Author(s):

Denis Comte ◽

Maria P. Karampetsou ◽

Katalin Kis-Toth ◽

Nobuya Yoshida ◽

Sean J. Bradley ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Regulatory T Cell ◽

Cell Activation ◽

Cell Polarization ◽

Systemic Lupus ◽

Signaling Lymphocytic Activation Molecule

Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4+ T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4+ T cells. Ligation of SLAMF3 receptors on SLE CD4+ T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.

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Autoantibodies specific for different isoforms of CD45 in systemic lupus erythematosus.

Journal of Experimental Medicine ◽

10.1084/jem.172.2.653 ◽

1990 ◽

Vol 172 (2) ◽

pp. 653-656 ◽

Cited By ~ 36

Author(s):

T Mimura ◽

P Fernsten ◽

W Jarjour ◽

J B Winfield

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Critical Role ◽

Antigenic Specificity ◽

Systemic Lupus ◽

Cd45 Isoforms

Nearly one-third of IgM antilymphocyte autoantibody-positive sera from patients with systemic lupus erythematosus (SLE) contain IgM antibodies to one or more 180-220-kD molecules (p180, p190, p205, and p220) in blots of glycoproteins purified from T cells by wheat germ agglutinin affinity chromatography. Identity of these IgM targets with multiple isoforms of CD45 was established by their specific depletion from T cell glycoproteins by immunoprecipitation with T191, a monoclonal antibody (mAb) that reacts with an epitope common to all CD45 isoforms. Although the anti-CD45 autoantibodies recognize higher molecular weight isoforms primarily, antigenic specificity in this system is quite heterogeneous and includes multiple distinct CD45 isoforms on different types of T cells that are, at least in part, different from those reactive with mAbs 2H4 and UCHL-1. Because CD45 is a major membrane protein tyrosine phosphatase that plays a critical role in antigen-induced T cell activation, the present data may be relevant to some of the antilymphocyte antibody-mediated immunologic abnormalities that characterize SLE and related autoimmune diseases.

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Boosting Antitumor Response by Costimulatory Strategies Driven to 4-1BB and OX40 T-cell Receptors

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.692982 ◽

2021 ◽

Vol 9 ◽

Author(s):

Daniele E. Mascarelli ◽

Rhubia S. M. Rosa ◽

Jessica M. Toscaro ◽

Isadora F. Semionatto ◽

Luciana P. Ruas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Activation ◽

Tumor Necrosis ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Tumor Control ◽

Antitumor Response ◽

Necrosis Factor

Immunotherapy explores several strategies to enhance the host immune system’s ability to detect and eliminate cancer cells. The use of antibodies that block immunological checkpoints, such as anti–programed death 1/programed death 1 ligand and cytotoxic T-lymphocyte–associated protein 4, is widely recognized to generate a long-lasting antitumor immune response in several types of cancer. Evidence indicates that the elimination of tumors by T cells is the key for tumor control. It is well known that costimulatory and coinhibitory pathways are critical regulators in the activation of T cells. Besides blocking checkpoints inhibitors, the agonistic signaling on costimulatory molecules also plays an important role in T-cell activation and antitumor response. Therefore, molecules driven to costimulatory pathways constitute promising targets in cancer therapy. The costimulation of tumor necrosis factor superfamily receptors on lymphocytes surface may transduce signals that control the survival, proliferation, differentiation, and effector functions of these immune cells. Among the members of the tumor necrosis factor receptor superfamily, there are 4-1BB and OX40. Several clinical studies have been carried out targeting these molecules, with agonist monoclonal antibodies, and preclinical studies exploring their ligands and other experimental approaches. In this review, we discuss functional aspects of 4-1BB and OX40 costimulation, as well as the progress of its application in immunotherapies.

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Review for "Tumor necrosis factor receptor family co‐stimulation increases regulatory T cell activation and function via NF‐κB"

10.1002/eji.201948393/v1/review1 ◽

2019 ◽

Keyword(s):

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Activation ◽

Regulatory T Cell ◽

Tumor Necrosis ◽

Cell Activation ◽

Tumor Necrosis Factor Receptor ◽

And Function ◽

Necrosis Factor ◽

Receptor Family

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Interleukin-22 and Tumor Necrosis Factor Receptor Associated Factor 1 (TRAF1) in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus: Correlation with Disease Activity

Egyptian Journal of Rheumatology and Clinical Immunology ◽

10.21608/ejrci.2015.4476 ◽

2015 ◽

Vol 3 (1) ◽

pp. 43-47

Author(s):

Eman Rashwan ◽

Mai Moaaz ◽

Nevine Mohannad ◽

Mohamed Rahman ◽

Eman Zaghloul

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Tumor Necrosis Factor ◽

Disease Activity ◽

Lupus Erythematosus ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Systemic Lupus ◽

Interleukin 22 ◽

Necrosis Factor

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Tumor necrosis factor receptor II and PTPN22 genes polymorphisms and the risk of systemic lupus erythematosus in Egyptian children

Lupus ◽

10.1177/09612033211020359 ◽

2021 ◽

pp. 096120332110203

Author(s):

Riham Eid ◽

Ayman Hammad ◽

Maha Abdelsalam ◽

Aya Ahmed Fathy ◽

Dena M Abd-El Ghafaar ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Tumor Necrosis Factor ◽

Lupus Erythematosus ◽

Tumor Necrosis ◽

Tyrosine Phosphatase ◽

Tumor Necrosis Factor Receptor ◽

Clinical Manifestations ◽

Systemic Lupus ◽

Egyptian Children ◽

Necrosis Factor

Background Many genes have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF) is a potent cytokine stimulator acting through 2 cell surface receptors (TNFR I and II). TNFRII gene which controls expression of these receptors has been linked to SLE susceptibility through promoting apoptosis. Also; Protein tyrosine phosphatase non receptor 22 (PTPN22) gene enhances intrinsic phosphatase activity of T lymphocytes leading to their dysregulation and stimulates autoimmune process of lupus and its rs2476601 has been linked to susceptibility to thyroiditis in SLE patients in few studies. Objectives (i) to investigate the correlation between 2 SNPs of TNFR II and PTPN22 genes and SLE susceptibility in a cohort of Egyptian children compared to controls (ii) and to investigate their possible association with different clinical presentations of the disease in children. Subjects and methods Typing of TNFR II rs1061622 and PTPN22 rs2476601 SNPs were done using polymerase chain reaction-restriction fragment length polymorphism for 74 children with SLE and 100 matched healthy controls. Results Children with SLE had more frequent G allele and GG genotype of TNFR II rs1061622 ( p < 0.001) and more T allele and TT genotype of PTPN22 rs2476601 ( p = 0.012 and <0.001, respectively) compared to controls. Only 6 patients (8%) had thyroiditis (hypothyroidism) with T allele and TT genotype of PTPN22 1858 T more prevalent in those patients versus those without thyroiditis ( p ≤ 0.001). Apart from, thyroiditis, no significant association was found between genotypes and alleles frequencies of the 2 studied SNPs and other clinical manifestations of the disease. Conclusion The G allele and GG genotype of TNFR II rs1061622 and T allele and TT genotype of PTPN22 rs2476601 genes polymorphism can be considered as risk factors for the development of SLE. The presence of the T allele of PTPN22 rs2476601 may increase the risk of concomitant thyroiditis in Egyptian children with SLE but further studies are required to confirm this finding as thyroiditis was reported only in few cases in this study.

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