Memory B cells are reactivated in subcapsular proliferative foci of lymph nodes

Abstract

Vaccine-induced immunity depends on the generation of memory B cells (MBC). However, where and how MBCs are reactivated to make neutralising antibodies remain unknown. Here we show that MBCs are prepositioned in a subcapsular niche in lymph nodes where, upon reactivation by antigen, they rapidly proliferate and differentiate into antibody-secreting plasma cells in the subcapsular proliferative foci (SPF). This novel structure is enriched for signals provided by T follicular helper cells and antigen-presenting subcapsular sinus macrophages. Compared with contemporaneous secondary germinal centres, SPF have distinct single-cell molecular signature, cell migration pattern and plasma cell output. Moreover, SPF are found both in human and mouse lymph nodes, suggesting that they are conserved throughout mammalian evolution. Our data thus reveal that SPF is a seat of immunological memory that may be exploited to rapidly mobilise secondary antibody responses and improve vaccine efficacy.

A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature

“…CCL20 has been linked to Innate Lymphoid Cell (ILC) trafficking across the SCS [14] and may affect the cross-talk between CCR6 positive DCs and LECs in antigen presentation [39]. CCL20 could also influence B-cell homeostasis, as memory B-cells precursors are distinguished by high CCR6 expression in lymphoid organs of both mouse and man [40] and are closely associated to the SCS [41]. CXCL1 may instead contribute to neutrophil migration and recruitment [42].…”

Germinal center B cell initiation, GC maturation, and the coevolution of its stromal cell niches

“…122 255 Although memory B cells have been reported to be positioned within lymphoid tissues at marginal zones, perifollicular zones, and some follicles after the resolution of response, 255,259,260 two studies have reported a predominant FM location for Ki67memory B cells in spleens and LNs. 249,250 Although the above studies support the idea that memory B cells primarily exit via follicle adjacent sinuses, it is worth noting that CCR6hi memory B cells are also responsive to CXCL12. 255…”

“…22,122 After the resolution of a primary response, both memory B cells and memory Tfh cells can be found within FMs, a positioning that is influenced by their EBI2 expression. 122,249,250 Theoretically, this compartment could influence the differentiative state of antigen-specific B cells that are leaving the GC via this route. As cells within this arena are less likely to be in active cell cycle, this environment may be more conducive to gaining a quiescent state, sheltered from the cellular interactions that promote a centroblast program and their self-renewal.…”

“…Intravital imaging has demonstrated that non-responding B cells are not excluded by a physical barrier and can move freely through GCs 70,72. After the resolution of a primary response, both memory B cells and memory Tfh cells can be found within FMs, a positioning that is influenced by their EBI2 expression 122,249,250. The follicular mantle harbors more than just non-responding B cells.…”

“…After the resolution of a primary response, both memory B cells and memory Tfh cells can be found within FMs, a positioning that is influenced by their EBI2 expression 122,249,250. Although memory B cells have been reported to be positioned within lymphoid tissues at marginal zones, perifollicular zones, and some follicles after the resolution of response,255,259,260 two studies have reported a predominant FM location for Ki67memory B cells in spleens and LNs 249,250. As cells within this arena are less likely to be in active cell cycle, this environment may be more conducive to gaining a quiescent state, sheltered from the cellular interactions that promote a centroblast program and their self-renewal.…”