: B Lymphocyte Induced Maturation Protein-1 (Blimp-1) is a transcriptional repressor with the unique property of being able to drive B cells to an immunoglobulin secreting, non-dividing, terminally differentiated plasma cell phenotype. In studying this protein our long-term goals are to: 1) understand how Blimp-1 functions during terminal B cell differentiation, 2) use Blimp-1 as an entry point to gain a better understanding of the regulatory mechanisms responsible for determining post-germinal center B cell fates and 3) identify universal mechanisms involved in terminal differentiation. In the current grant period we have made good progress in elucidating basic aspects of Blimp-1 's structure, regulation and mechanism of action and in identifying gene expression programs regulated by Blimp-1 in B cells. We have also created gene-targeted mice that will give rise to animals lacking Blimp-1 in mature B cells. We plan to exploit this progress by carrying out in-depth studies consisting of 4 specific aims. 1) Mice lacking Blimp-1 in their B cells will be used to determine if/when Blimp-1 is required for commitment to plasma cell fate. A thorough analysis of B cell development and function will be performed and the ability of Blimp-1 mutants or other transcription factors like XBP-1 to complement the Blimp-1-/- phenotype will be tested. Aging the mice will reveal if Blimp-1 has tumor suppressor activity in B cells. 2) Short-term culture systems in which germinal center B cells develop into memory or plasma cells will be used to learn when/how Blimp-1 and other transcriptional regulators are induced and act during commitment to these alternate fates. We will identify signals that direct their expression. 3) Established approaches will be used to determine if/how signals from IL-6, IL-10 and TNF/TNFRs activate Blimp-1 transcription. 4) Blimp-1's mechanism of gene repression may be unusual. We will study how DNA and histones are modified in target genes repressed by Blimp-1 and determine if Blimp-1 -dependent transcriptional repression is reversible when Blimp-1 is withdrawn. We will purify Blimp-1-containing repression complexes and identify the components of the complexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043576-10
Application #
7228563
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ferguson, Stacy E
Project Start
1998-06-01
Project End
2008-10-30
Budget Start
2007-05-01
Budget End
2008-10-30
Support Year
10
Fiscal Year
2007
Total Cost
$348,813
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
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
Martins, Gislaine; Calame, Kathryn (2008) Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol 26:133-69
Han, Jin-Hwan; Akira, Shizuo; Calame, Kathryn et al. (2007) Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors. Immunity 27:64-75
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
Tunyaplin, Chainarong; Shaffer, A L; Angelin-Duclos, Cristina D et al. (2004) Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 173:1158-65

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