Over the past several years, a number of factors have been shown to govern B cell immunopoeisis; I.E. the transition of naive B cells to GC B cells, memory B cells, isotype-switched B cells and B cells that have undergone somatic hypermutation. Unfortunately, there are no systems that can incisively evaluate each of these transitions because of the frequency of each of these events is so low. We present a system that will allow that exploration of these events at a high frequency. The novel features of the system that we present employs the use of 1) Ig-Tg B cells that using a site-directed rearrange VDJ inserted in the heavy chain locus with a well- defined specificity (nitrophenol, NP, known as quasi-monoclonal B cells QM); b) Tg CD4/+ T cells that can induce the differentiation of the QM B cells, c) the application of a series of reagents and knock-out mice that can selectively block the activities of factor shown to interfere with B cell immunopoeisis. The first specific aim is to define the characteristic changes that occur as QM B cells are driven to expand and differentiate in response to T cell help and a thymus-dependent antigen. For the first time, high frequencies of antigen-specific centroblasts, centrocytes, memory B cells and hyper- mutated B cells should be definable. It is anticipated that a more comprehensive understanding of the biology and regulation of each of these B cell subsets will be obtained. With this system in hand, the role of a series of relevant TNF family members in regulating discrete phases of B cell immunopoeisis will be studied. The impact of blocking factors known to be crucial to B cell immunopoeisis, like CD154, LTalpha, TNFalpha, OX40, and complement will be studied in detail. In parallel to studies of TD humoral immune responses in the QM system, development of the use of QM B cells to investigate studies of TD humoral immune responses in the QM system, development of the use of QM B cells to investigate thymus- independent (TI) immune responses will also be initiated. In contrast to TD responses, the response is to TI antigens is typified by low affinity anti-NP antibody. Conversion of the low affinity, non-anemnestic TI response to a high-affinity , anemnestic response will be achieve through the use of agonists that trigger TNFR family members (sCD154, anti-OX40, TNFalpha). Transitions from TI to TD-type responses will held resolve how each of these components influence B cell immunopoeisis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026296-13
Application #
6624615
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mallia, Conrad M
Project Start
1990-04-01
Project End
2004-02-29
Budget Start
2002-12-01
Budget End
2004-02-29
Support Year
13
Fiscal Year
2003
Total Cost
$322,818
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Elgueta, Raul; Marks, Ellen; Nowak, Elizabeth et al. (2015) CCR6-dependent positioning of memory B cells is essential for their ability to mount a recall response to antigen. J Immunol 194:505-13
Benson, Micah J; Elgueta, Raul; Schpero, William et al. (2009) Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals. J Exp Med 206:2013-25
Benson, Micah J; Dillon, Stacey R; Castigli, Emanuela et al. (2008) Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol 180:3655-9
Benson, Micah J; Erickson, Loren D; Gleeson, Michael W et al. (2007) Affinity of antigen encounter and other early B-cell signals determine B-cell fate. Curr Opin Immunol 19:275-80
Raman, Vanitha S; Lind, Evan F; Benson, Micah J et al. (2007) Strategies for selective priming of memory B cells. Immunol Lett 109:93-100
Hislop, Andrew D; Ressing, Maaike E; van Leeuwen, Daphne et al. (2007) A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates. J Exp Med 204:1863-73
O'Connor, Brian P; Vogel, Laura A; Zhang, Weijun et al. (2006) Imprinting the fate of antigen-reactive B cells through the affinity of the B cell receptor. J Immunol 177:7723-32
Noelle, Randolph J; Erickson, Loren D (2005) Determinations of B cell fate in immunity and autoimmunity. Curr Dir Autoimmun 8:1-24
O'Connor, Brian P; Raman, Vanitha S; Erickson, Loren D et al. (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199:91-8
O'Connor, Brian P; Gleeson, Michael W; Noelle, Randolph J et al. (2003) The rise and fall of long-lived humoral immunity: terminal differentiation of plasma cells in health and disease. Immunol Rev 194:61-76

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