During FY12 we accomplished the following: 1. Extended our studies of B cell priming by antigen. Short-term exposure of nave spleen B cells to antigen receptor (BCR) cross-linking makes them susceptible to receive T cell help via. CD40. We have previously shown that the memory of antigen priming lasts 6-9h in vitro and CD40 activation during this time leads to G1 progression as assayed by blast formation. We now extended the times of CD40 stimulation and found that B cell priming resulted in enhanced cell division. We found that the effects of short-term BCR cross-linking were evident 48-60h later in the form of increased cell division of primed cells. In the course of these studies we found that a subset of B cells continued to go through 2-3 cell divisions in the absence of exogenous signaling. We are currently further investigating this novel mode of cell-cycle control. 2. We initiated studies of mRNA half-life of NF-κB regulated genes in B lymphocytes. Additionally, we began to characterize mRNAs that were inducibly degraded as a consequence of BCR cross-linking. 3. We established conditions to carry out chromatin immunoprecipitation studies with anti-p65/RelA antibodies in primary mouse B cells. Using the IKBαpromoter as an established NF-κB-dependent target gene we found that p65/RelA ws recruited to the promoter within 45 minutes of BCR cross-linking and rapidly depleted from the promoter thereafter. These kinetics are consistent with IKBα-dependent nuclear export of NF-κB as a primary mode of down-regulating NF-κB activation. We propose to use this technique to study the kinetics of NF-κB binding and removal from genes in response to B cell activating stimuli on a genome-wide scale.
| Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2016) Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers. J Immunol 196:3385-97 |
| Kaileh, Mary; Vazquez, Estefania; MacFarlane 4th, Alexander W et al. (2016) mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes. PLoS One 11:e0146955 |
| Fowler, Trent; Garruss, Alexander S; Ghosh, Amalendu et al. (2015) Divergence of transcriptional landscape occurs early in B cell activation. Epigenetics Chromatin 8:20 |
| 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 |
| Kaileh, Mary; Sen, Ranjan (2012) NF-ýýB function in B lymphocytes. Immunol Rev 246:254-71 |
| Sen, Ranjan (2011) The origins of NF-?B. Nat Immunol 12:686-8 |
| Olkhanud, Purevdorj B; Damdinsuren, Bazarragchaa; Bodogai, Monica et al. (2011) Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4? T cells to T-regulatory cells. Cancer Res 71:3505-15 |
| Fowler, Trent; Sen, Ranjan; Roy, Ananda L (2011) Regulation of primary response genes. Mol Cell 44:348-60 |
| Damdinsuren, Bazarragchaa; Zhang, Yongqing; Khalil, Ashraf et al. (2010) Single round of antigen receptor signaling programs naive B cells to receive T cell help. Immunity 32:355-66 |
| Sen, Ranjan; Smale, Stephen T (2010) Selectivity of the NF-{kappa}B response. Cold Spring Harb Perspect Biol 2:a000257 |
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