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

Abstract

Objective Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4, CD244, 2B4) by its ligand SLAMF2 (CD48) modulates function and expansion of both NK cells and a subset of cytotoxic CD8+ T cells. As the cytotoxicity of CD8+ T lymphocytes isolated from systemic lupus erythematosus (SLE) patients is known to be impaired, we assess here whether expression and function of the checkpoint regulator SLAMF4 is altered on SLE CD8+ T cells. Methods Expression of SLAMF4 by healthy and SLE T cells was determined by Q-PCR and flow cytometry. T cells were activated with anti-CD3 antibody and degranulation activity was monitored by the surface expression of 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 is downregulated in CD8+ T cells from SLE patients as compared to cells obtained from healthy donors. Importantly, SLE patients have significantly fewer SLAMF4+ CD8+ T cells compared to healthy subjects. SLAMF4− CD8+ T cells from SLE patients have a decreased cytotoxic capacity and proliferative responses to viral peptides. The loss of memory SLAMF4+ CD8+ T cells in SLE patients is linked to the fact that they lose CD8 expression and become double negative T cells. Conclusion A selective loss of SLAMF4+ CD8+ T cells contributes to the compromised ability of SLE T cells to fight against infections.

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

“…Moreover, IL-2 plays a role in mounting adequate cytotoxic responses. This process is compromised in SLE patients, contributing to the increased rate of infection, one of the leading causes of morbidity and mortality in SLE (41,42). IL-2 also helps maintain peripheral immune self-tolerance by promoting activationinduced cell death (43), an important apoptotic process that contributes to the elimination of potentially autoreactive T cells.…”

T cells in Systemic Lupus Erythematosus

“…CD8 T cells in SLE have dampened cytotoxic function that can lead to increased risk of infection, which may also trigger autoimmunity [7]. Two recent studies showed defective CD8 responses to viral antigens, and proposed either a reduction in effector memory CD8 T cells positive for Signaling lymphocytic activation molecule family member 4 (SLAMF4) which is related to conversion of CD8 into double negative (DN) T cells [8], or increased expression of the inhibitory programmed death receptor 1 (PD-1) [9], an inhibitory receptor that is expressed under continuous TCR stimulation without co-stimulatory molecules. Induction of exhaustion has been proposed as therapy for autoimmune disease, as an exhaustion transcriptome profile marks patients with better clinical outcomes [10].…”

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.…”

“…Given the tremendous heterogeneity in SLE, it is plausible that different patients indeed have different pathological mechanisms. Although SLAMF4 loss could be conducive to loss of cytotoxic activity (34), genetic SLE-risk polymorphisms in the IL-12 pathway (35) associated with increased expression (36) may lead to increased cytotoxic activity. Our data are consistent with the reports of increased expression of cytotoxic mediators, although we also observe that ;10% of the lupus patients in both cohorts studied present reduced cytotoxic capacity.…”