We have recently shown that mature and immature B lymphocytes actively replicate upon transfer into B-cell deficient hosts (Cabatingan et.al. J. Immunol. 2002. 169:6765). This homeostatic B cell proliferation (B cell HP) is dependent on Bruton's tyrosine kinase (BTK), inhibited at high B cell densities, independent of antigen and T cells, active at low levels in normal hosts and distinct from more """"""""conventional"""""""" mitogenic responses as replicating cells retain a naive phenotype. New results show B cell HP absolutely requires BLyS (B lymphocyte stimulator) as a costimulator that induces the biochemical changes necessary to support B cell growth and division. BLyS stimulation is BTK-independent and synergizes with BTK-dependent inductive signals to initiate B cell HP. HP in B cells is a unique response to B cell deficit that may be important for maintaining B cell numbers and selectively expanding the naive B cell repertoire. The proposed studies will identify unique components of each of the signal pathways necessary for B cell HP, establish the interdependence of the BCR, the BLyS receptor (BR3) and B cell HP and determine the anatomical sites and cells necessary to support B cell HP.
Aim 1 is to determine the mechanism of HP signaling using pharmacological inhibitors to define critical components unique to the BTK-dependent inductive pathway and the BLyS dependent BTK-independent lymphotrophic pathway using separate in vitro assays specific for each process. The functional relevance of the signaling components initially identified in this screen will be confirmed using genetic approaches with in vitro and in vivo analyses.
Aim 2 is to determine the interactions between BCR and BR3, the two major nonredundant regulators of B cell homeostasis and B cell HP. Using BCR ablated and monoclonal B cell populations, we will determine if the BCR modulates HP by affectingBR3 expression or function and determine directly if the BCR can provide the BTK-dependent inductive signals required for HP thereby biasing the naive Ig repertoire.
Aim 3 is to identify the location and cells in the spleen that deliver the inductive and lymphotrophic signals necessary for B cell HP and to determine if ligands delivering these signals are unique to the spleen. Understanding the mechanism of B cell HP will provide new strategies for effecting immune reconstitution in the aged or immunodeficient or following chemotherapy or recovery from lymphotoxic infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Experimental Immunology Study Section (EI)
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Esch, Thomas R
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University of Massachusetts Medical School Worcester
Schools of Medicine
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McGinnes Cullen, Lori; Schmidt, Madelyn R; Kenward, Sarah A et al. (2015) Murine immune responses to virus-like particle-associated pre- and postfusion forms of the respiratory syncytial virus F protein. J Virol 89:6835-47
Schmidt, Madelyn R; McGinnes-Cullen, Lori W; Kenward, Sarah A et al. (2014) Modification of the respiratory syncytial virus f protein in virus-like particles impacts generation of B cell memory. J Virol 88:10165-76
Schmidt, Madelyn R; McGinnes, Lori W; Kenward, Sarah A et al. (2012) Long-term and memory immune responses in mice against Newcastle disease virus-like particles containing respiratory syncytial virus glycoprotein ectodomains. J Virol 86:11654-62
Castro, Iris; Wright, Jacqueline A; Damdinsuren, Bazarragchaa et al. (2009) B cell receptor-mediated sustained c-Rel activation facilitates late transitional B cell survival through control of B cell activating factor receptor and NF-kappaB2. J Immunol 182:7729-37
Alugupalli, Kishore R; Leong, John M; Woodland, Robert T et al. (2004) B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity 21:379-90
Alugupalli, Kishore R; Gerstein, Rachel M; Chen, Jianzhu et al. (2003) The resolution of relapsing fever borreliosis requires IgM and is concurrent with expansion of B1b lymphocytes. J Immunol 170:3819-27