Ly9 (CD229) Cell-Surface Receptor is Crucial for the Development of Spontaneous Autoantibody Production to Nuclear Antigens

Abstract

The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demonstrate that the SLAMF member Ly9 arises as a novel receptor contributing to the reinforcement of tolerance. Specifically, Ly9-deficient mice spontaneously developed features of systemic autoimmunity such as the production of anti-nuclear antibodies (ANA), -dsDNA, and -nucleosome autoantibodies, independently of genetic background [(B6.129) or (BALB/c.129)]. In aged (10- to 12-month-old) Ly9−/− mice key cell subsets implicated in autoimmunity were expanded, e.g., T follicular helper (Tfh) as well as germinal center (GC) B cells. More importantly, in vitro functional experiments showed that Ly9 acts as an inhibitory receptor of IFN-γ producing CD4+ T cells. Taken together, our findings reveal that the Ly9 receptor triggers cell intrinsic safeguarding mechanisms to prevent a breach of tolerance, emerging as a new non-redundant inhibitory cell-surface receptor capable of disabling autoantibody responses.

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

“…A recent study has shown that Ly9 (SLAMF3)-deficient mice develop spontaneous autoimmunity, and that in vitro anti-CD3-and anti-CD28-stimulated CD4 + T cells from Ly9-deficient mice exhibit greater IFNγ production compared with their wild type counterparts, suggesting SLAMF3 involvement in protection against autoimmunity (9).…”

Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production

“…Sle1b [ Sle1b ] and B6.1 29chr1b [129chr1b] develop autoantibodies linked to polymorphisms of SLAMF1-7 molecules (14) (15). SLAMF3-deficient mice (129xBALB/c) spontaneously develop autoimmune characteristics including autoantibodies against nuclear antigens, aberrant cytokine production and splenomegaly (16) and SLAMF1, 5 and 6 serve as negative regulators of humoral immune response (17). …”

B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

“…Polymorphisms in the Ly108/Slamf6 gene are implicated in the loss of early B cell (4) as well as peripheral T cell-mediated tolerance (5). Several independent studies have suggested the contribution of three other SLAMF genes, Slamf1 (SLAM/CD150), Slamf2 (CD48) and Slamf3 (Ly9) in autoimmunity (6–8). However, the role of B cell-intrinsic expression of different isoforms of Ly108 or other SLAM receptors in the regulation of B cell tolerance at the germinal center (GC) checkpoint remains unclear.…”

“…Because Slamf genes are genetically linked, it has been difficult to determine the potential role of polymorphisms in a specific family member in autoimmunity using knockout mice generated in an autoimmune 129 background that are subsequently backcrossed to B6 (6–8, 12, 13). It is also unclear whether non- Slamf genes located in Sle1b contribute to a break in B cell tolerance given the presence of non-synonymous mutations in these genes in autoimmune B6.…”