Primary antibody production and generation of B-cell memory are two essential components for protective immunity to pathogen. Our previous analysis of the primary and memory response to (T,G)-A--L showed that primary antibody secretion and memory generation are separable events: no primary antibodies are made to the AL epitope, however, AL-specific memory B-cells are generated, they constitute 20-30% of the anti-(T,G)-A--L memory response, and they produce antibody upon memory recall. The signals which determine whether the primary B-cell differentiates to primary antibody secretion or enter the memory pathway are not known. We hypothesized that the nature and strength of the signal transduced by the B-cell receptor (BCR) is key, and that low affinity BCRs is signal for entry to the memory pathway but not for Ig secretion. This hypothesis will be tested by examining the cellular and molecular outcomes of activating primary B-cells whose BCRs differ in epitope specificity and affinity, using VDJ knock-in mice made by recombination. The primary-AL knock-in will express the VDJ from a primary, AL-specific B-cell, the secondary AL knock-in will express that cell's mutated heavy chain (memory cell), and the primary-GT knock-in will express the VDJ from a primary GT-specific B-cell. The physiological outcome of activating these primary B-cells will be established, with emphasis on determining whether the primary-Al, primary-GT and secondary-AL B-cells can form extrafollicular foci, primary antibody forming cells germinal centers and memory B-cells, either in situ or after adoptive cell transfer. in vitro activation studies with these knock-in B-cells will establish whether antigen-specific stimulation leads to similar or different patterns of response, as measured by proliferation, surface phenotype, Ig secretion, and nuclear translocation of transcription factors. The role of Btk in signaling low affinity B-cells for primary antibody secretion vs. memory formation will be examined using xid-VDJ-knock-ins. The results of these studies will aid our understanding of the B-cell activation signals for antibody secretion and memory, and thus provide information helpful in the design of vaccines for multi-determinant pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunobiology Study Section (IMB)
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Kerr, Lawrence D
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Brandeis University
Schools of Arts and Sciences
United States
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Maul, Robert W; Cao, Zheng; Venkataraman, Lakshmi et al. (2014) Spt5 accumulation at variable genes distinguishes somatic hypermutation in germinal center B cells from ex vivo-activated cells. J Exp Med 211:2297-306
Giorgetti, C A; Press, J L (1998) Somatic mutation in the neonatal mouse. J Immunol 161:6093-104
Mainville, C A; Sheehan, K M; Klaman, L D et al. (1996) Deletional mapping of fifteen mouse VH gene families reveals a common organization for three Igh haplotypes. J Immunol 156:1038-46
Giorgetti, C A; Press, J L (1994) A peptide sequence mimics the epitope on the multideterminant antigen (Tyr,Glu)-Ala-Lys that induces the dominant H10/V kappa 1+ primary antibody response. J Immunol 152:136-45
Press, J L; Giorgetti, C A (1993) Molecular and kinetic analysis of an epitope-specific shift in the B cell memory response to a multideterminant antigen. J Immunol 151:1998-2013
Press, J L; Giorgetti, C A; Busby 3rd, W F (1991) A new germline VH36-60 gene is used in the neonatal primary and adult memory response to (T,G)-A--L. Mol Immunol 28:1217-24
Borriero, L; Giorgetti, C; Smith, G et al. (1990) Neonatal and adult primary B cells use the same germ-line VH and V kappa genes in their (T,G)-A-L-specific repertoire. J Immunol 144:583-92
Busto, P; Gerstein, R; Dupre, L et al. (1987) Molecular analysis of heavy and light chains used by primary and secondary anti-(T,G)-A--L antibodies produced by normal and xid mice. J Immunol 139:608-18
Press, J L; Giorgetti, C A (1986) Clonal analysis of the primary and secondary B cell responses of neonatal, adult, and xid mice to (T,G)-A--L. J Immunol 137:784-90
Busto, P; Giorgetti, C A; Gawoski, J et al. (1986) Xid and normal mice express a light chain-associated cross-reactive idiotype in response to (T,G)-A--L and (T,G)-A--L-mBSA. J Immunol 136:3734-43