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

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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MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus

Cells ◽

10.3390/cells8111433 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1433 ◽

Cited By ~ 7

Author(s):

Chuang ◽

Tan

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Cell Signaling ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Therapeutic Targets ◽

T Cell Signaling ◽

Systemic Lupus

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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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

Arthritis & Rheumatism ◽

10.1002/art.20038 ◽

2004 ◽

Vol 50 (2) ◽

pp. 629-639 ◽

Cited By ~ 31

Author(s):

Hwei-Fang Tsai ◽

Jiann-Jyh Lai ◽

Ai-Hsiang Chou ◽

Ting-Fang Wang ◽

Chien-Sheng Wu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Tumor Necrosis ◽

Cell Activation ◽

Systemic Lupus ◽

Necrosis Factor

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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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Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus

Clinical & Experimental Immunology ◽

10.1111/cei.12657 ◽

2015 ◽

Vol 182 (1) ◽

pp. 1-13 ◽

Cited By ~ 15

Author(s):

J. P. Mackern-Oberti ◽

J. Obreque ◽

G. P. Méndez ◽

C. Llanos ◽

A. M. Kalergis

Keyword(s):

Systemic Lupus Erythematosus ◽

Carbon Monoxide ◽

T Cell ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Systemic Lupus ◽

Target Organs

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Cytokine Overproduction, T-Cell Activation, and Defective T-Regulatory Functions Promote Nephritis in Systemic Lupus Erythematosus

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/457146 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 33

Author(s):

Marco Tucci ◽

Stefania Stucci ◽

Sabino Strippoli ◽

Francesco Silvestris

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

B Cells ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Cell Function ◽

Inflammatory Cells ◽

Systemic Lupus ◽

Regulatory Functions

Lupus nephritis (LN) occurs in more than one-third of patients with systemic lupus erythematosus. Its pathogenesis is mostly attributable to the glomerular deposition of immune complexes and overproduction of T helper- (Th-) 1 cytokines. In this context, the high glomerular expression of IL-12 and IL-18 exerts a major pathogenetic role. These cytokines are locally produced by both macrophages and dendritic cells (DCs) which attract other inflammatory cells leading to maintenance of the kidney inflammation. However, other populations including T-cells and B-cells are integral for the development and worsening of renal damage. T-cells include many pathogenetic subsets, and the activation of Th-17 in keeping with defective T-regulatory (Treg) cell function regards as further event contributing to the glomerular damage. These populations also activate B-cells to produce nephritogenic auto-antibodies. Thus, LN includes a complex pathogenetic mechanism that involves different players and the evaluation of their activity may provide an effective tool for monitoring the onset of the disease.

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