The overall goal of this PPG is to understand how SLAM family (Slamf) members control pathways that regulate the development of systemic lupus erythematosus (SLE). Project 2 will investigate the role of SLAMF2 (CD48) interactions with its binding partner SLAMF4 (CD244,2B4) in controlling immune cell function, establishment and maintenance of tolerance and development of SLE immune cell abnormalities. Based on our published and preliminary data we hypothesize that SLAMF2 and SLAMF4 regulate T cell and APC function, control immune tolerance, and contribute to autoimmunity-related pathology in mice and patients with SLE. Studies in mice and patients with SLE will test this hypothesis by performing complementary and closely interactive experiments.
o Specific Aim #1 : To test the hypothesis that Slamf4 on the surface of mouse APC regulates the balance between T cell activation and tolerance in the pathogenesis of SLE.
o Specific Aim #2 : To test the hypothesis that Slamf2 regulates the balance between T cell activation and tolerance in the pathogenesis of SLE.
o Specific Aim #3 : To test the hypothesis that the SLAMF2 and SLAMF4 receptors function aberrantly in peripheral blood immunocytes isolated from SLE patients.
Our mechanistic studies (genetic manipulation of S1-AI /IF2 and 4 in mice and silencing in human immunocytes), coupled with in vivo and in vitro use of stimulatory and inhibitory Abs, will generate proposals for therapeutic interventions in human SLE and therefore underscore the significance of the proposed studies.
|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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