Linking signaling and selection in the germinal center

Abstract

Germinal centers (GC) are sites of rapid B-cell proliferation in response to certain types of immunization. They arise in about 1 week and can persist for several months. In GCs, B cells differentiate in a unique way and begin to undergo somatic mutation of the Ig V regions at a high rate. GC B cells (GCBC) thus undergo clonal diversification that can affect the affinity of the newly mutant B-cell receptor (BCR) for its driving antigen. Through processes that are still poorly understood, GCBC with higher affinity are selectively expanded while those with mutations that inactivate the BCR are lost. In addition, at various times during the extended GC reaction, some GCBC undergo differentiation into either long-lived memory B cells (MBC) or plasma cells. The cellular and molecular signals that govern these fate decisions are not well-understood, but are an active area of research in multiple laboratories. In this review, we cover both the history of this field and focus on recent work that has helped to elucidate the signals and molecules, such as key transcription factors, that coordinate both positive selection as well as differentiation of GCBC.

Keywords: B cells; B-cell receptor; CD40; affinity maturation; c-Myc.

Fig. 1:. Hybrid Model of GCBC Selection

Successful competition for antigen binding of dark zone GCBCs with are of sufficient affinity results in the generation of p-foxo1 through BCR mediated PI3K/Akt signaling (a) which promotes initial migration of these cells and “licenses” them to remain in the light zone. Additionally, BCR signaling may induce anti-apoptotic factors (b) which allow more time for the partly selected GCBCs to productively interact with cognate T_FH cells. Upon such interaction, BCR and CD40 signaling synergistically lead to the expression of c-Myc and the activation of the mTORC1 pathway which induces the phosphorylation of S6, therefore fully engaging the process of positive selection (c). Positively selected LZ GCBCs migrate towards the DZ and their induced mTORC1-driven anabolic state readies them for intensive proliferation, which coincides with the acquisition of additional mutations catalyzed by AID. As c-Myc protein levels are diluted out with each cell division (d) DZ GCBCs need to be successful in binding to antigen in order to undergo another cycle of selection. Proliferating DZ GCBCs that fail to bind to antigen due to mutation-mediated reduced BCR affinity or function will undergo apoptosis.