CD23+CD21highCD1dhigh B Cells in Inflamed Lymph Nodes Are a Locally Differentiated Population with Increased Antigen Capture and Activation Potential

Abstract

CD23+CD21highCD1dhigh B cells (Bin cells) accumulate in the LNs draining inflamed joints of the TNFα transgenic (TNFtg) mouse model of rheumatoid arthritis, and are primarily involved in the significant histological and functional LN alterations that accompany disease exacerbation in this strain. Here we investigate the origin and function of Bin cells. We show that adoptively transferred GFP+ sorted mature follicular B (FoB) cells home preferentially to inflamed LNs of TNFtg mice where they rapidly differentiate into Bin cells, with a close correlation with the endogenous Bin fraction. Bin cells are also induced in wild-type (WT) LNs after immunization with T-dependent antigens, and display a germinal center phenotype at higher rates compared to FoB cells. Furthermore, we show that Bin cells can capture and process antigen immune complexes in a CD21-dependent manner more efficiently than FoB cells, and express higher levels of MHCII and costimulatory antigens CD80 and CD86. We propose that Bin cells are a previously unrecognized inflammation-induced B cell population with increased antigen capture and activation potential, which may facilitate normal immune responses but may contribute to autoimmunity when chronic inflammation causes their accumulation and persistence in affected LNs.

TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes

“…In order to more specifically test the involvement of TNFR1/2 signals in the generation of Bin cells in the TNF-tg arthritis model, we carried out adoptive transfer of sorted, CFSE-loaded CD23+ CD21/35-low splenic follicular B cells into TNF-tg mice with overt arthritis in the hind and front paws, and then assessed their Bin differentiation in the draining lymph nodes (popliteal, and brachial plus axillary). As previously demonstrated, under these conditions the transferred follicular B cells acquire a Bin phenotype in inflamed LNs within 24–48 hours of transfer, and do so at percentages that closely correlate with the fraction of endogenous Bin cells in the same nodes [6]. Adoptively transferred TNFR1/2KO B cells behaved in the same fashion, showing proportional, quantitative differentiation into Bin cells within recipient nodes (Fig.…”

“…We have previously shown that differentiation of Bin cells from sorted follicular B cells occurs selectively, quantitatively and rapidly (48hrs) within the inflammatory milieu of TNF-tg LNs draining arthritic joints [6]. We therefore considered whether continuous stimulation with TNF and/or inflammatory stimuli is required to maintain the Bin phenotype.…”

“…As immunization, and even adjuvant injection alone, are sufficient to induce differentiation of Bin-phenotype cells in WT draining lymph nodes [6], we proceeded to test whether any TNF receptor-mediated signals are required for differentiation of Bin cells in the context of immunization. We carried out footpad immunization in mice deficient for both TNF receptors (TNFR1/2KO) and wild-type controls, and 15 days post-immunization we analyzed resident B cell populations in the draining lymph nodes, using contralateral nodes as controls.…”

“…2) suggests that the balanced cross-talk of these two receptors, via their differential ligand specificities and signaling pathways, may in fact play a role in modulating Bin-originating signals, either directly or via effects on the inflammatory microenvironment. Altogether, these findings could explain the quantitative and kinetics differences of Bin cell generation observed in immunized vs. TNF-tg lymph nodes [6], and could have implications for the pathological outcomes in acutely vs. chronically inflamed lymph nodes.…”

“…Consistent with this model, we have previously shown that progressive joint inflammation in the TNF transgenic (TNF-tg) mouse model of inflammatory-erosive arthritis is accompanied by an increase in draining lymph node’s size, cellularity and drainage capacity, and that disease flares (as detected by increased synovial volume) and bone erosion at the knees are preceded by a rapid decrease in drainage capacity and substantial structural remodeling of the affected nodes [2–5]. These changes are specifically associated with unique alterations in the resident B cell population within the reactive nodes, resulting in the local differentiation of a follicular B cell-derived subset with a unique CD23+, CD21/35-high, CD1d-high, IgM-high, IgD-high phenotype and increased ability to capture and process antigen immune complexes ( B cell in i nflamed n odes, or Bin cells) [4–6]. Most significantly from a pathogenic standpoint, Bin cells localize to, and substantially occupy paracortical sinusoids in collapsed TNF-tg lymph nodes, likely contributing to the decreased lymphatic drainage function of the nodes [2–5, 7, 8].…”