Fat-associated lymphoid clusters control local IgM secretion during pleural infection and lung inflammation

Abstract

Fat-associated lymphoid clusters (FALC) are inducible structures that support rapid innate-like B-cell immune responses in the serous cavities. Little is known about the physiological cues that activate FALCs in the pleural cavity and more generally the mechanisms controlling B-cell activation in FALCs. Here we show, using separate models of pleural nematode infection with Litomosoides sigmodontis and Altenaria alternata induced acute lung inflammation, that inflammation of the pleural cavity rapidly activates mediastinal and pericardial FALCs. IL-33 produced by FALC stroma is crucial for pleural B1-cell activation and local IgM secretion. However, B1 cells are not the direct target of IL-33, which instead requires IL-5 for activation. Moreover, lung inflammation leads to increased IL-5 production by type 2 cytokine-producing innate lymphoid cells (ILC2) in the FALC. These findings reveal a link between inflammation, IL-33 release by FALC stromal cells, ILC2 activation and pleural B-cell activation in FALCs, resulting in local and antigen-specific IgM production.

Fat-Associated Lymphoid Clusters in Inflammation and Immunity

“…Both myeloid cell precursors (CD31/ER-MP58 + ) and mature macrophages (F4/80 + ) have been detected in omental FALCs, suggesting that these lymphoid clusters form permissive microenvironments where the former cells can proliferate locally to be a source of free macrophages within the peritoneal cavity (32). A similar process is likely to take place in FALCs in the mediastinum and pericardium (33, 34). Importantly, FALCs contain type 2 innate lymphoid cells (ILC2) that can support the proliferation of B1 cells through the expression of IL-5 (19).…”

“…These cytokines are produced in response to IL-33 and IL-25 and promote goblet cell hyperplasia and helminth expulsion (19, 48). Likewise, a recent report has shown that medFALCs and perFALCs respond to both lung infection with the nematode Litomosoides sigmodontis and lung inflammation via fungal allergen inhalation (33). Under these conditions, medFALC stromal cells produce IL-33, which leads to ILC2 activation and IL-5 secretion.…”

“…Under these conditions, medFALC stromal cells produce IL-33, which leads to ILC2 activation and IL-5 secretion. This in turn promotes the recruitment and activation of B cells and culminates in the production of natural IgM antibodies (Ab) for local protection (33). …”

Immunological Functions of the Omentum

“…Innate lymphoid cells (ILCs), particularly ILC2 cells, are also found in adipose tissues, including the omentum [15, 24]. Like VAT-associated Tregs, ILC2 cells express ST2 and respond to local IL-33 [15].…”

“…Like VAT-associated Tregs, ILC2 cells express ST2 and respond to local IL-33 [15]. Interestingly, the IL-33-induced expression of IL-5 by ILC2 cells in the FALCs of the pericardium promotes the differentiation of local B1 B cells into IgM-secreting cells [15]. Given that ILC2 cells are also present in the omentum, a similar process likely occurs in this location [47].…”