Strawberry notch homologues in T cell homeostasis and function

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Abstract Effective and long lasting antibody responses, which require delicate collaboration from both T and B cells, is essential for immune responses to antigens and successful vaccinations against microbial infections; however, the mechanisms that regulate T cell function in antibody responses are still not fully understood. In addition, hypogammaglobinemia is the hallmark of common variable immunodeficiency (CVID), which can result in repetitive infections and even death of children and is the most common symptomatic primary immune deficiency in adults with causal factors in most patients still elusive. Via whole genome exon sequencing, we have identified a mis-sense mutation in the Strawberry Notch homologue 2 (SBNO2) gene. SBNO1/2 are conserved nuclear proteins belonging to the DExD/H RNA helicase family. Their orthologue, strawberry notch (SNO), functions downstream of Notch/Hippo pathways and is important for embryogenesis, oogenesis, and development of the eye, wing and leg in drosophila. However, the functions of SBNO1/2 in mammals, especially in the immune system, and whether these two proteins perform overlapping functions are virtually unknown. We have generated a novel mouse model, Sbno2m/m, that harbors a CVID mutation in the endogenous Sbno2 gene and conditional Sbno1 and Sbno2 deficient mice. With strong preliminary data from these mice, we hypothesize that Sbno1/2 are critical players in T cells for their development and function, particularly in T cell-mediated antibody and anti-viral immune responses. We will 1) determine the roles of Sbno1 and Sbno2 for T cell development and homeostasis, 2) determine the role of Sbno1 and Sbno2 in T cell mediated immune responses, and 3) investigate the mechanisms underlying Sbno1/2- mediated immune regulation. The proposed studies are expected to illustrate novel mechanisms that control T cell development, homeostasis, and function to shape antibody and anti-viral immune responses. By illustrating the importance of Sbno1/2 in T cells, we will provide insight into mechanisms underlying T cell biology and CVID that will guide the development of novel therapeutic strategies against immune-related disorders.