Genetic studies have implicated the SLAM family in Systemic lupus erythematosus (SLE), but the? functional roles of specific gene(s) within the SLAM locus in SLE are not yet clear. Our recent studies? show that CD48 deficient (-/-) mice backcrossed onto the C57BL/6 (B6) background from the 129Sv? background for 12 generations develop a lupus-like syndrome. By 6 months of age, these CD48-/- mice? develop activated T and B cells, anti-nuclear antibodies, immune complexes and glomerulonephritis. We? also have found that there are defects in T cell tolerance in CD48-/- mice. There are 2 potential? explanations for the development of the SLE phenotype: Disease could be caused by the absence of? CD48, or due to epistatic interactions between 129Sv genes flanking the disrupted CD48 gene and B6? genes in the CD48-/- mouse strain. The goal of Project 3 is to investigate the role of CD48 in SLE. As a? definitive tool to understand the essential functions of CD48, we will use CD48-/- B6 mice generated by? homologous recombination using B6 ES cells.
Our specific aims are: 1) To test the hypothesis that? CD48 regulates antigen-specific CD4 T cell activation and tolerance. We will examine if there are? intrinsic T cell defects and/or dysregulated interactions between APC and T cells. We also use CD244-/-? mice to investigate whether the CD48 ligand, CD244, regulates T cell responses. This focus on CD244? is driven by genetic studies of Project 1 that implicate CD244 variation in human SLE and preliminary? data that suggest CD244 on the APC may regulate T cell: APC interactions. 2) To test the hypothesis? that CD48 regulates B cell activation and/or B cell tolerance. We will determine if there are B cell? intrinsic defects, examine humoral immune responses, and generate CD48-/- VH3H9 transgenic mice to? study the role of CD48 in regulating anti-dsDNA B cells. 3) To investigate the hypothesis that CD48? regulates the development of SLE. We determine whether SLE develops in B6 CD48-/- mice. If SLElike? disease develops, then we will evaluate the function of CD48 on the T cell, B cell and other cell? types in SLE. If SLE does not develop, we will test the hypothesis that CD48-/-(129Sv x B6)BC12 CD48-? /- mice develop SLE due to flanking 129Sv SLAM family genes and not due to the disrupted CD48 gene,? by introducing a 129Sv BAG with a normal or disrupted 129Sv CD48 gene into the CD48-/- C57BL/6? mouse and assess whether the resulting strains develop SLE. This PPG facilitates collaborative? interactions and provides a number of important tools and approaches that will enable us to address? these important issues. These studies should contribute to the overall goal of this PPG: to understand? how SLAM family members control pathways that regulate the development of SLE.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Beth Israel Deaconess Medical Center
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Cuenca, Marta; Puñet-Ortiz, Joan; Ruart, Maria et al. (2018) Ly9 (SLAMF3) receptor differentially regulates iNKT cell development and activation in mice. Eur J Immunol 48:99-105
Comte, Denis; Karampetsou, Maria P; Yoshida, Nobuya et al. (2017) Signaling Lymphocytic Activation Molecule Family Member 7 Engagement Restores Defective Effector CD8+ T Cell Function in Systemic Lupus Erythematosus. Arthritis Rheumatol 69:1035-1044
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2017) Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2. Arthritis Rheumatol 69:808-813
Sage, Peter T; Ron-Harel, Noga; Juneja, Vikram R et al. (2016) Suppression by TFRcells leads to durable and selective inhibition of B cell effector function. Nat Immunol 17:1436-1446
Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin et al. (2016) Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production. J Immunol 196:4915-24
Cuenca, Marta; Romero, Xavier; Sintes, Jordi et al. (2016) Targeting of Ly9 (CD229) Disrupts Marginal Zone and B1 B Cell Homeostasis and Antibody Responses. J Immunol 196:726-37
Kis-Toth, Katalin; Comte, Denis; Karampetsou, Maria P et al. (2016) 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. Arthritis Rheumatol 68:164-73
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2016) Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A 113:9321-6
McArdel, Shannon L; Brown, Daniel R; Sobel, Raymond A et al. (2016) Anti-CD48 Monoclonal Antibody Attenuates Experimental Autoimmune Encephalomyelitis by Limiting the Number of Pathogenic CD4+ T Cells. J Immunol 197:3038-3048
McArdel, Shannon L; Terhorst, Cox; Sharpe, Arlene H (2016) Roles of CD48 in regulating immunity and tolerance. Clin Immunol 164:10-20

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