Signaling Lymphocytic Activation Molecule Family Member 7 Engagement Restores Defective Effector CD8+ T Cell Function in Systemic Lupus Erythematosus

Abstract

Objective Effector CD8+ T cell function is impaired in SLE and associated with compromised ability to fight infections. SLAMF7 engagement has been shown to enhance NK cell degranulation. Thus, we characterized the expression and function of SLAMF7 on CD8+ T cells subsets isolated from peripheral blood of SLE patients and healthy subjects. Methods CD8+ T cell subset distribution, SLAMF7 expression and cytolytic enzyme expression (perforin, GzmA, GzmB) were monitored on cells isolated from SLE patients and healthy controls by flow cytometry. CD107a expression and IFNγ production in response to viral antigenic stimulation were assessed by flow cytometry in the presence or absence of an anti-SLAMF7 antibody. The antiviral cytotoxic activity in response to SLAMF7 engagement was determined using a flow cytometry-based assay. Results The distribution of CD8+ T cell subsets is altered in the peripheral blood of SLE patients with decreased effector cell subpopulation. Memory CD8+ T cells from SLE patients display decreased amounts of SLAMF7, a surface receptor that characterizes effector CD8+ T cells. Ligation of SLAMF7 increases CD8+ T cell degranulation capacity and the percentage of IFNγ-producing cell in response to antigen challenge in SLE and healthy controls. Moreover, SLAMF7 engagement promotes cytotoxic lysis of target cells in response to viral antigenic stimulation. Conclusion Activation of SLAMF7 through a specific mAb restores defective SLE effector CD8+ T cells function in response to viral antigens and represents a potential therapeutic option in SLE.

A Systemic Lupus Erythematosus Endophenotype Characterized by Increased CD8 Cytotoxic Signature Associates with Renal Involvement

“…Reports of both increased expression of cytotoxic mediators (9) need to be contrasted with those that have reported reduced cytotoxicity and/or exhaustion (8,21,34). Given the tremendous heterogeneity in SLE, it is plausible that different patients indeed have different pathological mechanisms.…”

“…CD8 + T cells have been extensively studied in autoimmune diseases such as type 1 diabetes, where cytotoxic mechanisms are a central part of the pathology. However, there is limited and often contradictory understanding of how CD8 + T cells or cytotoxic mechanisms contribute to SLE pathology, as both an increase and a decrease in cytotoxic activity have been described in lupus (8,9). CD8 + CD57 + T cells, which are increased in lupus, have been associated with immune senescence and exhaustion given their reduced telomeric length, proliferative capacity, and loss of the costimulatory molecule CD28 (10).…”

Hypomethylation ofSTAT1andHLA-DRB1is associated with type-I interferon-dependentHLA-DRB1expression in lupus CD8+ T cells

“…While the epigenetic components of CD8+ T cells in lupus have yet to be described, the regulatory and functional changes of CD8+ T cells in lupus have been previously examined. Among total CD8+ T cells, lupus patients with active disease have increased proportion of naïve CD8+ T cells and reduced proportion of effector CD8+ T cells [6, 7]. Effector CD8+ T cells in lupus patients have reduced effector functionality through altered cytokine production, diminished suppressor function, and decreased cytotoxic T cell activity [6, 8].…”

“…Among total CD8+ T cells, lupus patients with active disease have increased proportion of naïve CD8+ T cells and reduced proportion of effector CD8+ T cells [6, 7]. Effector CD8+ T cells in lupus patients have reduced effector functionality through altered cytokine production, diminished suppressor function, and decreased cytotoxic T cell activity [6, 8]. The cytokine profiles of lupus CD8+ T cells have been found to favor increased IL-12 and decreased IL-6, thus resulting in dysregulation of the stimulatory and inhibitory roles of CD8+ T cells, respectively [8].…”

“…The cytokine profiles of lupus CD8+ T cells have been found to favor increased IL-12 and decreased IL-6, thus resulting in dysregulation of the stimulatory and inhibitory roles of CD8+ T cells, respectively [8]. In addition, CD8+ T cells in lupus patients are characterized by reduced expression of signaling lymphocytic activation molecule family member 7 (SLAMF7), which is a type I transmembrane glycoprotein receptor that promotes effector CD8+ T cell function [6]. In contrast, Blanco et al reported that patients with SLEDAI scores of seven or greater had a diminished naïve CD8+ T cell population and an elevated effector CD8+ T cell population [9].…”