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. 2019 Jul 2;10:1400. doi: 10.3389/fimmu.2019.01400

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Copyright © 2019 Auladell, Jia, Hensen, Chua, Fox, Nguyen, Doherty and Kedzierska.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Pathways to B cell memory. Naïve B cells become activated by direct recognition of antigens expressed on the surface of the pathogen. Top panel: Follicular (FO) naïve B cells become activated within the lymph node through a T cell-dependent pathway. CD4⁺ T cells become activated by recognizing viral peptides processed by FO dendritic cells and presented on their surface by MHC-II molecules. After becoming activated, both CD4⁺ T cells and B cells, travel to the T-B border in the lymph node, where they interact. Three outcomes can follow this interaction. (i) A germinal center (GC) is formed, CD4⁺ T cells polarize into T follicular helper (Tfh) cells and FO B cells differentiate into GC B cells. In the GC, B cells undergo rapid proliferation and somatic hypermutation of the Ig V regions in their B cell receptors (BCR), due to their interaction with Tfh cells through CD40-CD40L, PD1-PD-L1/L2, ICOS-ICOSL among others and the secretion of cytokines such as IL-4 and IL-21, affinity maturation takes place and those B cells that increase affinity toward their Ag are selected. Some of these B cells will also class-switch. These interactions result in the generation of IgM⁺ memory B cells (B_MEM), IgG⁺/A⁺/E⁺ B_MEM or IgG/A/E secreting long-lived plasma cells (LLPC) in this order in time. The later these cells are generated, the higher affinity and lesser cross-reactivity they have toward the antigen or antigen variants, respectively. (ii) Not all B cells enter the GC after interacting with their cognate activated CD4⁺ T cells in the T-B border, IgM⁺ B_MEM and IgM secreting LLPCs are also generated outside of the GC, in a GC-independent (GCi) manner. (iii) Short-lived antibody secreting cells (ASC) are generated early after activation to generate a rapid response against the pathogen. These short-lived ASC will undergo apoptosis and do not contribute to the generation of B cell memory. Bottom panel: Some protein antigens provide highly repetitive antigenic structures, which induce strong BCR crosslinking. Viral single-stranded RNA (ssRNA) together with other danger signals also activate toll-like receptors such as TLR7. These strong signals are enough to activate B cells in a T cell-independent (TI) manner and generate short-lived IgM secreting ASC and IgM⁺ B_MEM. B1b and marginal zone (MZ) B cells are activated in a TI manner and provide a faster response against the pathogen.