Cells of the myeloid lineage play critical roles in both innate and adaptive immunity. This application is designed to elucidate the role, molecular mechanism of action and regulation of B Lymphocyte Induced Maturation Protein-1 (Blimp-1) in myeloid lineage cells. Blimp-1 is a zinc finger-containing transcriptional repressor that is known to play a key role in commitment and differentiation of B lymphocytes to plasma cells. However, our recent studies have shown that Blimp-1 is also expressed in monocytes and granulocytes and induced upon macrophage differentiation of promyeloid lines and primary bone marrow progenitors. Furthermore, it is required and sufficient to trigger macrophage differentiation of U937 promonocytes. Therefore, Blimp-1 is likely to be a critical regulator of macrophage differentiation and function and may also be important for the differentiation and/or function of other myeloid lineage cells. The project has three specific aims. First, we will use gene targeting and expression of inhibitory forms of Blimp-1 to determine the ability of myeloid cells to differentiate and function in the absence of Blimp-1. These studies are designed to establish the role of BLIMP-1 in macrophages, granulocytes and myeloid dentritic cells. Second, we will exploit microarray technology to characterize Blimp-1 -dependent programs of gene expression during macrophage and granulocyte differentiation. Further studies will be performed to identify direct targets of Blimp-1 and to compare them among myeloid and B lymphocyte lineages. Finally, the signals and mechanisms responsible for regulation of Blimp-1 expression in myeloid cells will be studied.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI050659-01
Application #
6418441
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Nasseri, M Faraz
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$403,901
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Rutishauser, Rachel L; Martins, Gislâine A; Kalachikov, Sergey et al. (2009) Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31:296-308
Martins, Gislaine A; Cimmino, Luisa; Liao, Jerry et al. (2008) Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J Exp Med 205:1959-65
Magnusdottir, Erna; Kalachikov, Sergey; Mizukoshi, Koji et al. (2007) Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1. Proc Natl Acad Sci U S A 104:14988-93
Kuo, Tracy C; Shaffer, Arthur L; Haddad Jr, Joseph et al. (2007) Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med 204:819-30
Savitsky, David; Calame, Kathryn (2006) B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. J Exp Med 203:2305-14
Martins, Gislaine A; Cimmino, Luisa; Shapiro-Shelef, Miriam et al. (2006) Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 7:457-65
Shapiro-Shelef, Miriam; Lin, Kuo-I; Savitsky, David et al. (2005) Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J Exp Med 202:1471-6
Shaffer, A L; Shapiro-Shelef, Miriam; Iwakoshi, Neal N et al. (2004) XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21:81-93
Shapiro-Shelef, Miriam; Calame, Kathryn (2004) Plasma cell differentiation and multiple myeloma. Curr Opin Immunol 16:226-34
Shapiro-Shelef, Miriam; Lin, Kuo-I; McHeyzer-Williams, Louise J et al. (2003) Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19:607-20

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