IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs

Abstract

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions. IL-22 | tertiary lymphoid organs | chemokines | Sjogren's syndrome | autoimmunity

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…In particular IL-22 could upregulate CXCL13 and CXCL12 in tertiary lymphoid organs, thus favoring B-cell recruitment and autoantibody production. 49 In addition, IL-17 drives the differentiation of IL-17Rc…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…For example, IL‐23 is linked with ectopic lymphoid neogenesis in rheumatoid arthritis 22. Through control of lymphoid chemokine production in epithelial and fibroblastic stromal cells, IL‐22 also drives lymphoid neogenesis in mice following salivary gland cannulation with adenovirus 23. Podoplanin and IL‐17 have also been linked with ectopic lymphoneogenesis in human diseases 21, 24, 25…”

“…Recent studies have implicated novel T helper cell subsets as initiators of ELF formation. Given the role that cytokines play in the regulation of T helper cell differentiation and effector function, a number of cytokines have now been linked with the control of ELF s. For example, cytokines involved in the regulation of T helper type 17 (Th17) cell responses ( IL ‐6, IL ‐21, IL ‐23, IL ‐27, IL ‐2, IL ‐22, IL ‐17)23, 137, 139, 145, 148, 152 and follicular T helper (Tfh) cell responses [ IL ‐6, IL ‐21, Type I interferons ( IFN s), IL ‐27, IL ‐2]137, 139, 146, 147, 150 are emerging as regulators of lymphoid neogenesis. Here we highlight cytokines that may positively (red) and negatively (blue) control ELF s based on their ability to regulate effector T‐cell populations involved in ELF development or function.…”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…A similar context‐dependent role for IL‐17 in TLS development is observed in models of autoimmunity. Th17 cells and IL‐17 play a prominent role in the development of TLSs during experimental autoimmune encephalomyelitis,35 but are not central to lymphoid neogenesis in inflamed salivary glands 38. Our data illustrates that while GC development in gp130 F/F mice is linked with the heightened expression of the Th17‐associated markers Il17a , Il23 and Rorγt ,30 the signature Th17 cytokine IL‐17 is not required for gastric tumourigenesis or the development of submucosal TLSs.…”

“…Notably, while STAT3 phosphorylation was clearly detected in TLSs, STAT3 activation was not confined to these sites but was also found in areas of diffuse lymphocyte infiltration. Therefore, despite a role for STAT3 activating cytokines in lymphoid neogenesis,4, 21, 23, 38, 39 localised STAT3 activity remains a poor indicator of TLS involvement.…”