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The role of danger signal and cellular competition in the elimination of B cells lacking the B cell receptor.

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.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/genome

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)
Address
Robert Rossle Strasse 10
13125 Berlin
Germany
Activity type
Research Organisations
EU contribution
€ 171 460,80