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Objective 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. Methods CD8+ T cell subset distribution, SLAMF7 expression, and expression of cytolytic enzymes (perforin, granzyme A [GzmA], and GzmB) on cells isolated from SLE patients and healthy controls were analyzed by flow cytometry. CD107a expression and interferon-γ (IFNγ) production in response to viral antigenic stimulation in the presence or absence of an anti-SLAMF7 antibody were assessed by flow cytometry. Antiviral cytotoxic activity in response to SLAMF7 engagement was determined using a flow cytometry-based assay. Results The distribution of CD8+ T cell subsets was altered in the peripheral blood of SLE patients, with a decreased effector cell subpopulation. Memory CD8+ T cells from SLE patients displayed decreased amounts of SLAMF7, a surface receptor that characterizes effector CD8+ T cells. Ligation of SLAMF7 increased CD8+ T cell degranulation capacity and the percentage of IFNγ-producing cells in response to antigen challenge in SLE patients and healthy controls. Moreover, SLAMF7 engagement promoted cytotoxic lysis of target cells in response to stimulation with viral antigens. Conclusion CD8+ T cell activation in response to viral antigens is defective in SLE patients. Activation of SLAMF7 through a specific monoclonal antibody restores CD8+ T cell antiviral effector function to normal levels and thus represents a potential therapeutic option in SLE. [ABSTRACT FROM AUTHOR]

Objective 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. Methods The expression of SLAMF4 by T cells from healthy donors and patients with SLE was determined by quantitative polymerase chain reaction and flow cytometry. T cells were activated with anti-CD3 antibody, and degranulation activity was monitored by the surface expression of lysosome-associated membrane protein 1 (LAMP-1; CD107a). The SLAMF4+ and SLAMF4− CD8+ T cell subpopulations were characterized by LAMP-1, perforin, and granzyme B expression and viral peptide-induced proliferation. Results SLAMF4 gene and surface protein expression was down-regulated in CD8+ T cells from SLE patients compared with that in cells obtained from healthy donors. Importantly, SLE patients had significantly fewer SLAMF4+ CD8+ T cells compared with healthy donors. SLAMF4− CD8+ T cells from SLE patients had a decreased cytotoxic capacity and decreased proliferative responses to viral peptides. The loss of memory SLAMF4+ CD8+ T cells in SLE patients was linked to the fact that these cells have an increased propensity to lose CD8 expression and become double-negative T cells. Conclusion A selective loss of SLAMF4+ CD8+ T cells contributes to the compromised ability of T cells from patients with SLE to fight infection. [ABSTRACT FROM AUTHOR]

Objective To identify microRNAs (miRNAs) in human T cells that can explain known antiinflammatory properties of steroids. Methods Activated human CD4+ T cells from healthy donors were exposed to 1 μ M methylprednisolone (MP) in vitro and then subjected to miRNA and messenger RNA microarray analyses. Changes in expression profiles were recorded. Using quantitative polymerase chain reaction (qPCR), flow cytometry, and enzyme-linked immunosorbent assay (ELISA), we confirmed the suppression of predicted targets, and through miRNA transfection experiments, we could suggest mechanistic links. Results We identified numerous steroid-responsive genes and miRNAs-many known and some novel-including multiple previously unknown proinflammatory genes suppressed by MP. Further studies using qPCR, flow cytometry, and ELISA demonstrated that methylprednisolone increased the expression of miRNA-98 (miR-98) and suppressed the levels of predicted targets, including interleukin-13 and 3 tumor necrosis factor receptors (TNFRs): Fas, FasL, and TNFR superfamily member 1B. Forced expression of miR-98 in T cells resulted in suppression of the same targets. Conclusion The findings of this study demonstrate a link between miR-98 expression and the effects of MP and provide evidence suggesting that MP acts through miR-98 to inhibit specific proinflammatory targets. Identification of this antiinflammatory mechanism of glucocorticoids is important, since it may pave the way toward the elusive goal of dissociating adverse effects from therapeutic effects. [ABSTRACT FROM AUTHOR]

The CD28 co-stimulatory pathway is well established for T cell activation. However, there is evidence suggesting the existence of additional co-stimulatory pathways. Here we report that a member of the SLAM superfamily, SLAMF6, or CD352 plays an important role in T cell co-stimulation. Cross-linking of SLAMF6 with anti-CD3 primes human T cell to secrete Th1 cytokines. Among the T cell subsets, CD8++ and CD3++CD4−−  CD8−−  cells display the highest Th1 production responses. Engagement of SLAMF6 mobilizes the modulation of the same set of NF-κκB-associated genes. Although the expression of SLAMF6 on the surface of T cells from patients with systemic lupus erythematosus (SLE) T cells is comparable to that on the normal T cells, engagement of SLAMF6 results in severely reduced Th1 and IL-2 cytokine production. Our results suggest the existence of an additional co-stimulatory pathway in human T cells, which is defective in SLE T cells. [ABSTRACT FROM AUTHOR]

The article talks about a study conducted to determine whether inhibition of calcium/calmodulin-dependent protein kinase type IV (CaMKIV) would improve systemic lupus erythematosus (SLE), which can be treated by the use of indiscriminate immunosuppression. The data was collected with KN-93, a CaMKIV inhibitor on MRL/lpr mice by evaluating the impact of lessening of CAMK4 on interferon-γ (IFN-γ) expression by human SLE T cells.