SLAMF molecules are involved in the expression and regulation of multiple aspects ofthe innate and adaptive immune response. Work in mice carried out under the auspices of this Program have revealed important roles in the expression of autoimmunity, and more importantly, lupus-related pathology. Interestingly, disputed SLAMF-llnked single nucleotide polymorphism (SNP) associations have been reported in patients with systemic lupus erythematosus (SLE) while the expression of SLAMF isoforms and their modulatory role on immune cell function has not been studied systematically. We hypothesize that the expression of isoforms of SLAMF is aberrant in Immune cells in SLE patients and that their homotypic engagement leads to aberrant immune cell function including cytokine and autoantibodyproduction. To test this hypothesis we propose experiments grouped in four Specific Alms.
The significance of the proposed work is that it points out to the need to consider blockade of the homotypic SLAMF Interaction to suppress autoimmunity. This project borrows concepts from Projects 1 and 2 and provides direct feedback for murine preclinical studies.
|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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