Maria P. Karampetsou

T cells as a therapeutic target in SLE

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion, and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell-targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE.

Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4–Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus

Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4; CD244, 2B4) by its ligand SLAMF2 (CD48) modulates the function and expansion of both natural killer cells and a subset of cytotoxic CD8+ T cells. Because the cytotoxicity of CD8+ T lymphocytes isolated from patients with systemic lupus erythematosus (SLE) is known to be impaired, the aim of this study was to assess whether the expression and function of the checkpoint regulator SLAMF4 are altered on CD8+ T cells from patients with SLE.

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

Significance Systemic lupus erythematosus (SLE) is characterized by compromised IL-2 production and regulatory T-cell function. Studies in human SLE and in murine lupus models report that IL-2 replenishment ameliorates clinical lupus manifestations. Here we show that engagement of signaling lymphocytic activation molecule family 3 (SLAMF3), a coregulatory receptor of T cells, restores the sensitivity of SLE CD4+ T cells to IL-2, increasing their response to exogenous IL-2 via up-regulation of the IL-2Rα subunit. Moreover, activation of naïve CD4+ T cells with a monoclonal antibody directed against SLAMF3 promotes T helper cell differentiation toward a suppressive phenotype. These data suggest that the SLAMF3 receptor may be a promising therapeutic target in SLE. 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.

Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2

Imbalanced cytokine production by T cells characterizes both patients with systemic lupus erythematosus (SLE) and lupus‐prone mice and contributes to immune dysregulation. This study was undertaken to further investigate in detail the production of interleukin‐2 (IL‐2), interferon‐γ (IFNγ), IL‐4, and IL‐17A by CD4+ cell subsets in healthy subjects and patients with SLE, and the signaling response of CD4+ T cells in response to exogenous IL‐2.

ICER is requisite for Th17 differentiation

Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

CD4+ T cells from SLE patients respond poorly to exogenous IL‐2

Imbalanced cytokine production by T cells characterizes both patients with systemic lupus erythematosus (SLE) and lupus‐prone mice and contributes to immune dysregulation. This study was undertaken to further investigate in detail the production of interleukin‐2 (IL‐2), interferon‐γ (IFNγ), IL‐4, and IL‐17A by CD4+ cell subsets in healthy subjects and patients with SLE, and the signaling response of CD4+ T cells in response to exogenous IL‐2.

Signaling Lymphocytic Activation Molecule Family Member 7 Engagement Restores Defective Effector CD8+ T Cell Function in Systemic Lupus Erythematosus: SLAMF7 ENHANCES SLE CD8+ T CELL FUNCTION

Effector CD8+ T cell function is impaired in systemic lupus erythematosus (SLE) and is associated with a compromised ability to fight infections. Signaling lymphocytic activation molecule family member 7 (SLAMF7) engagement has been shown to enhance natural killer cell degranulation. This study was undertaken to characterize the expression and function of SLAMF7 on CD8+ T cell subsets isolated from the peripheral blood of SLE patients and healthy subjects.

SLAMF7 engagement restores defective effector CD8+ T cells activity in response to foreign antigens in systemic lupus erythematosus

Effector CD8+ T cell function is impaired in systemic lupus erythematosus (SLE) and is associated with a compromised ability to fight infections. Signaling lymphocytic activation molecule family member 7 (SLAMF7) engagement has been shown to enhance natural killer cell degranulation. This study was undertaken to characterize the expression and function of SLAMF7 on CD8+ T cell subsets isolated from the peripheral blood of SLE patients and healthy subjects.

Expression patterns of signaling lymphocytic activation molecule family members in peripheral blood mononuclear cell subsets in patients with systemic lupus erythematosus.

Genome-wide linkage analysis studies (GWAS) studies in systemic lupus erythematosus (SLE) identified the 1q23 region on human chromosome 1, containing the Signaling Lymphocytic Activation Molecule Family (SLAMF) cluster of genes, as a lupus susceptibility locus. The SLAMF molecules (SLAMF1-7) are immunoregulatory receptors expressed predominantly on hematopoietic cells. Activation of cells of the adaptive immune system is aberrant in SLE and dysregulated expression of certain SLAMF molecules has been reported. We examined the expression of SLAMF1-7 on peripheral blood T cells, B cells, monocytes, and their respective differentiated subsets, in patients with SLE and healthy controls in a systematic manner. SLAMF1 levels were increased on both T cell and B cells and their differentiated subpopulations in patients with SLE. SLAMF2 was increased on SLE CD4+ and CD8+ T cells. The frequency of SLAMF4+ and SLAMF7+ central memory and effector memory CD8+ T cells was reduced in SLE patients. Naïve CD4+ and CD8+ SLE T cells showed a slight increase in SLAMF3 levels. No differences were seen in the expression of SLAMF5 and SLAMF6 among SLE patients and healthy controls. Overall, the expression of various SLAMF receptors is dysregulated in SLE and may contribute to the immunopathogenesis of the disease.

SLAMF1 engagement inhibits T cell-B cell interaction and diminishes IL-6 production and plasmablast differentiation in systemic lupus erythematosus

Signaling lymphocytic activation molecule family member 1 (SLAMF1) homophilic interactions promote immunoglobulin production and T cell–B cell cross‐talk. SLAMF1 is overexpressed on T and B cells in patients with systemic lupus erythematosus (SLE). This study was undertaken to determine the role of SLAMF1 monoclonal antibody (mAb) in modulating T cell–B cell interaction and B cell activation.