The goal of the proposed project is to characterize differences in human B1 and B2 lymphocyte differentiation and to determine if IL-7/IL-7R interactions play a role in B2 versus B1 cell fate determination. B1 and B2 lymphocytes perform complementary roles in immune function and predominate at different points in ontogeny. B1 cells predominate early in life and generate polyreactive antibodies that provide protection from common bacterial pathogens. B1 cells are associated with autoimmune diseases and have been implicated as critical regulators of autoimmune responses. Several functional and phenotypic differences between B1 and B2 lymphocytes have been identified in the mouse, however, human B1 cells are poorly characterized. Mice defective in IL-7 production have a complete block in B2 differentiation, but normal numbers of B1 cells. However, the mechanism that determines B1 versus B2 differentiation is controversial. Preliminary studies support a model of B2 versus B1 differentiation that incorporates aspects of both historical models. Preliminary studies suggest that cord blood (CB) contains an IL-7R-B cell differentiation pathway that is absent in adult bone marrow (BM). The following hypotheses are proposed: 1) human B1 and B2 cells arise from distinct progenitors that predominate at different points in ontogeny, 2)expression of the IL-7R distinguishes human B2 from B1 lymphocyte progenitor populations, and 3) events downstream of IL7/IL-7R interactions promote human B2 versus B1 differentiation. Hypotheses will be tested using three experimental approaches. First, phenotypic and functional characteristics that distinguish mature human B1 and B2 cells will be determined. Second, B1 and B2 differentiation from human CB and BM progenitor populations will be studied in vitro, in the immunodeficient mouse xenograft model, and by examining B1 and B2 cell recovery in stem cell transplant patients. Third, the role of IL-7/IL-TR interactions in B1 and B2 differentiation will be examined by using IL-7 blocking antibodies in B cell differentiation assays and by characterizing B cells from patients defective in IL-7R signaling. Through the proposed project the applicant will gain knowledge of immune function and training in a variety of cellular and molecular techniques that will be applied as an independent investigator to understanding the role of the immune system in disease states.
|Parrish, Yasmin Khan; Baez, Ineavely; Milford, Terry-Ann et al. (2009) IL-7 Dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. J Immunol 182:4255-66|
|Popescu, Marcela; Gurel, Zafer; Ronni, Tapani et al. (2009) Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. J Biol Chem 284:13869-80|
|Gurel, Zafer; Ronni, Tapani; Ho, Sam et al. (2008) Recruitment of ikaros to pericentromeric heterochromatin is regulated by phosphorylation. J Biol Chem 283:8291-300|
|Luo, Peihua; Wang, Anxun; Payne, Kimberly J et al. (2007) Intrinsic retinoic acid receptor alpha-cyclin-dependent kinase-activating kinase signaling involves coordination of the restricted proliferation and granulocytic differentiation of human hematopoietic stem cells. Stem Cells 25:2628-37|
|Ronni, Tapani; Payne, Kimberly J; Ho, Sam et al. (2007) Human Ikaros function in activated T cells is regulated by coordinated expression of its largest isoforms. J Biol Chem 282:2538-47|
|Zhang, Yanjia; Payne, Kimberly J; Zhu, Yuhua et al. (2005) SCL expression at critical points in human hematopoietic lineage commitment. Stem Cells 23:852-60|