Review ArticleSignaling lymphocyte activation molecule family in systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is a complex, multifactorial and potentially life threatening autoimmune disease of unknown etiology affecting mainly young women of reproductive age. A combination of hormonal, genetic, epigenetic and environmental factors are implicated in the break of tolerance to self-antigen which characterizes SLE [1]. In very rare cases, single-gene defects, the most common among them being deficiencies in early complement activation components (C2, C3, C1q) may be sufficient in driving the development of systemic autoimmunity [2,3]. However, SLE is a genetically complex disease with a variety of gene defects and/or polymorphisms that contribute to the overall genetic susceptibility.
T cells and B cells signaling abnormalities as well as dysregulated interactions between these two cell populations lead to aberrant immune cell function and eventually to the production of autoantibodies and organ damage [[4], [5], [6]]. Despite significant progress made over the past decades in understanding the molecular and biochemical events that lead to the abnormal activation of the immune system in lupus, management of SLE still relies on the use of corticosteroids and non-specific immunosuppressive agents, thus making the need to discover newer, safer and more effective treatments mandatory.
Activation, proliferation and differentiation of T cells are determined by tightly controlled interactions between antigen-presenting cells (APC) and T lymphocytes. Three different types of signals have been described to play major roles in the modulation of the T cell receptor (TCR) signaling and response: (i) antigen recognition, (ii) co-stimulation and co-inhibition (iii) effect of cytokines [7,8]. The best-characterized co-stimulation pathway involves the CD28 co-stimulatory receptor on T cells. After ligation by its natural ligands, B7-1 (CD80) or B7-2 (CD86) on APC, CD28 signaling enhances the T cell response. The activation of CD28 is counterbalanced by co-inhibitory molecules. Programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are two major, well characterized co-inhibitory molecules that are expressed on T cells following activation. These co-inhibitory molecules can be directly or indirectly targeted to modulate the immune response [9]. Many other costimulatory molecules have been described and shown to deliver co-stimulatory or co-inhibitory signals upon T or B cell activation, including SLAMF (signaling lymphocyte activation molecule family) [10]. SLAMF represents a complex family of surface co-receptors that is comprised of nine different members (SLAMF1-9) belonging to the CD2 superfamily of immunoglobulin domain-containing molecules. These members include SLAMF1 (CD150 or SLAM), SLAMF2 (CD48), SLAMF3 (CD229 or Ly9), SLAMF4 (CD244 or 2B4), SLAMF5 (CD84), SLAMF6 (CD352, NTBA or SF2000 in human or Ly108 in mice), SLAMF7 (CD319, CS1 or CRACC). The gene encoding SLAMF8 (CD353 or BLAME) and SLAMF9 (CD84-H1 or SF2001) are located in close proximity to the main SLAMF gene cluster [11]. SLAMF receptors are composed of an extracellular segment (with two to four Ig-like domains), a transmembrane domain and a cytoplasmic tail [10]. The cytoplasmic domain of SLAMF members contains one to four intracellular switch motif amino acid sequences (ITSM). SLAMF2, SLAMF8 and SLAMF9 differ structurally compared to the rest of the SLAMF members in the sense that SLAMF2 is a glycophosphatidylinositol (GPI)-anchored protein with no transmembrane or cytoplasmic domain [12], whereas the cytoplasmic domains of SLAMF8 and SLAMF9 are short and do not contain ITSM sequences [13].
One of the most interesting and unique features of the SLAMF members is that they act as self ligands, interacting with one another in a homotypic manner, with exception of SLAMF2 whose ligand is SLAMF4 and CD2, albeit with lower affinity. Upon SLAMF engagement, the ITSM sequence recruits its adaptor molecules SLAM-associated protein (SAP) or Ewing's sarcoma's/FLI1-activated transcript 2 (EAT-2) to mediate downstream signaling [10,12].
Genome-wide analysis studies (GWAS) have identified at least 50 loci conferring to lupus susceptibility [14]. Studies using gene mapping methods conducted during the early 2000s [15,16] identified the 1q23 chromosomal region, which encodes for the SLAMF receptors, as a highly polymorphic region and as a susceptibility locus for SLE. Moreover, studies in different murine models of spontaneous autoimmunity (NZB/WF1, NZM, BXSB strains) showed a strong connection between the genomic 1H3 region, which in mice is the syntenic genomic region of human 1q23, and severe lupus manifestations [[17], [18], [19]]. In humans, single nucleotide polymorphisms and specific SLAMF variants have been associated with rheumatoid arthritis, neuropsychiatric SLE and lupus nephritis, thus further highlighting the importance of 1q23 region and potential involvement of SLAMF members in systemic autoimmunity [[20], [21], [22], [23]].
To this date, only a limited number of studies have systematically addressed the expression of SLAMF receptors and/or the in vitro effect of specific anti-SLAMF monoclonal antibodies on SLE T and B cells [[24], [25], [26], [27], [28], [29], [30], [31]]. In this review, we present current data and future directions on the role of SLAMF members in SLE (Table 1).
Section snippets
SLAMF1
T cells, B cells and dendritic cells express SLAMF1, while SLAMF1 is not expressed by monocytes and NK cells [32,33]. On T cells, and especially on CD4+ T cells, SLAMF1 expression increases with cell differentiation, displaying a low level of expression on naïve cells and higher levels of expression on effector and memory cells [24]. SLAMF1 is also upregulated following T and B cell activation, suggesting that the expression of this receptor may reflect the activation status of several
SLAMF2
From a structural point of view, SLAMF2 is unique compared to the rest of the SLAMF members in that it does not possess a cytoplasmic tail, yet upon interaction with SLAMF4 or CD2 it elicits downstream signaling in a mechanism that still remains unclear [36]. SLAMF2 is an integral component of the lipid rafts. Its co-engagement enhances early TCR-initiated responses by facilitating actin cytoskeleton reorganization and recruitment of associated lipid rafts to the TCR associated activation cap [
SLAMF3
The extracellular segment of SLAMF3 is slightly different compared to other SLAMF members, being composed of four Ig-like domains (2 tandem repeats of V-like regions and C2-like regions) [12]. Recent data in humans have shown that SLAMF3 is expressed at a high level on CD4+, CD8+, double negative (DN) T cells, B cells and, at a lower level, on NK cells [24,27]. On CD4+ and CD8+ T cells, SLAMF3 expression has been observed on every differentiated CD4+ and CD8+ T cell subset from naïve to
SLAMF4
Compared to other SLAMF receptors, SLAMF4 does not interact through a homophilic interaction, but is activated after it binds SLAMF2, its natural ligand. SLAMF4 expression is mainly reported on cytotoxic cells. On CD8+ T cells, its expression is up-regulated while cells acquire a differentiated phenotype, with almost 100% of terminally differentiated effector memory cells expressing SLAMF4 [24,28]. To some extent, it follows the expression pattern of immune inhibitory receptors, such as PD-1,
SLAMF5
SLAMF5 is expressed on all hematopoietic cells [12]. Data regarding the role of SLAMF5 in SLE are limited and mostly focused on its expression on cells of innate and adaptive immunity. T cells isolated from patients with biopsy-proven lupus nephritis displayed decreased expression of SLAMF3, SLAMF5 and SLAMF7 on the cell surface of CD8+ and DN in patients who were in remission compared to patients with active nephritis [25]. Decreased expression of SLAMF5 has also been reported on circulating
SLAMF6
Most studies evaluating expression levels of SLAMF6 on hematopoietic cells did not detect any significant differences between SLE and healthy donors. Moreover, few studies assessed its function in humans or SLE in particular [24,30]. In one study, which focused on a small cohort of SLE patients, an increased expression of SLAMF6 on T cells has been reported and co-engagement of SLAMF6 with a specific anti-SLAMF6 monoclonal antibody has been associated with increased TNFα, IFNγ and IL-17
SLAMF7
SLAMF7 is expressed on NK cells, NK T cells, CD8+ T cells, DN T cells, plasma cells, macrophages and dendritic cells [10,60]. On CD8+ T cells, SLAMF7 follows a similar pattern of expression to SLAMF4, which is a high expression level on effector memory and terminally differentiated effector memory cells, while its expression is low on naïve CD8+ T cells [24,61]. The frequency of SLAMF7 expressing CD4+ T is very low (less than 5%), whereas almost 100% of NK cells are positive for SLAMF7 [24,29,45
SAP
Upon engagement, SLAMF receptors interact with SAP (SLAM associated protein, SH2D1A), a highly conserved, non-polymorphic cytoplasmic SH2-domain-containing molecule [12]. It is predominantly expressed in T cells, NK cells, NKT cells, eosinophils and platelets.
Absence or loss-of-function mutations of SAP result in a rare primary immunodeficiency, known as XLP (X-linked lymphoproliferative disease) [12]. Fulminant infectious mononucleosis is the most common clinical presentation of XLP and is
Conclusions
Members of the SLAM family of co-receptors appear to play an important role in immune regulation involved in autoimmune diseases and more specifically in SLE. Recent findings emphasize that SLAMF molecules may be implicated in the mechanisms involved in the proliferation, differentiation and maintenance of hematopoietic cells, especially lymphocytes, by playing a role as co-stimulatory or co-inhibitory molecules that regulate cell fate after activation. SLAMF is a complex and redundant system
Funding
This work was supported by a grant from the Swiss National Science Foundation Ambizione PZ00P3_173950 (to D.C.)
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