Objective B cells represent a specialized population of lymphocytes responsible for adaptive immune responses and life-long immune memory. All mature B cells carry B cell receptors (BCRs) on the surface and it is through the BCR that B cells recognize foreign antigens and subsequently provide antibody responses. Acute ablation of the BCR in resting mature naïve B cells in mice leads to a fast disappearance of Immunoglobulin negative (Ig-) B cells from peripheral lymphoid system. This phenomenon has been mainly explained by a “tonic” signal provided by the BCR, essential for B cell survival. However, there are at least two other possible, not mutually exclusive, mechanisms. In this proposal I hypothesize that i) loss of the BCR structure provides a “danger” signal leading to apoptosis of Ig- B cells; ii) Ig- B cells are eliminated as a result of cellular competition with the Ig+ B cells. I will test these 2 hypothesis by i) addressing the unfolded protein response (UPR) in Ig- B cells as a possible “danger signal” followed by in vivo genetic rescue experiments testing for its causality in Ig- B cell depletion; ii) I will produce pure Ig- B cell cultures, exploiting the novel system of genome editing of primary B cells, and address - in vitro and in vivo - the fitness, proliferation and differentiation capacity of Ig- B cells in presence and absence of cellular competition with Ig+ B cells. By addressing these points my work might provide a first-time evidence for the existence of “a danger signal” initiated in a B cell upon BCR ablation and prove its causality in Ig- B cell disappearance. On the other hand, elimination of Ig- B cells as a result of cellular competition with Ig+ B cells is a novel concept with important implications for lymphoma biology and potential clinical applications. Fields of science medical and health sciencesmedical biotechnologygenetic engineeringgene therapynatural sciencesbiological sciencescell biologynatural sciencesphysical sciencesopticsmicroscopyelectron microscopymedical and health sciencesbasic medicineimmunologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2016 - Individual Fellowships Call for proposal H2020-MSCA-IF-2016 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC) Net EU contribution € 171 460,80 Address Robert rossle strasse 10 13125 Berlin Germany See on map Region Berlin Berlin Berlin Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
