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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.

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Topic(s)

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Funding Scheme

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MSCA-IF-EF-ST - Standard EF

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2016

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Coordinator

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 171 460,80
Address
ROBERT ROSSLE STRASSE 10
13125 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Research Organisations
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 171 460,80
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