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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI065687-08
Application #
8733824
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Wang, Ninghai; Keszei, Marton; Halibozek, Peter et al. (2016) Slamf6 negatively regulates autoimmunity. Clin Immunol 173:19-26
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; Terhorst, Cox; Sharpe, Arlene H (2016) Roles of CD48 in regulating immunity and tolerance. Clin Immunol 164:10-20
Chaudhary, Anu; Leite, Mara; Kulasekara, Bridget R et al. (2016) Human Diversity in a Cell Surface Receptor that Inhibits Autophagy. Curr Biol 26:1791-801
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
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
Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih et al. (2016) A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells. Oncotarget 7:26346-60
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
Wang, Guoxing; van Driel, Boaz J; Liao, Gongxian et al. (2015) Migration of myeloid cells during inflammation is differentially regulated by the cell surface receptors Slamf1 and Slamf8. PLoS One 10:e0121968
O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4

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