Lymphotoxin Controls the IL-22 Protection Pathway in Gut Innate Lymphoid Cells during Mucosal Pathogen Challenge

Abstract

Summary Innate lymphoid cells (ILCs) have emerged as important players regulating the balance between protective immunity and immunopathology at mucosal surfaces. However, mechanisms that regulate ILCs effector functions during mucosal pathogenic challenge are poorly defined. Using mice infected with the natural mouse enteric pathogen Citrobacter rodentium, we demonstrate that lymphotoxin (LT) is essential for IL-22 production by intestinal ILCs. Blocking of LTβR signaling dramatically reduced intestinal IL-22 production after C. rodentium infection. Conversely, stimulating LTβR signaling induced IL-22 protection pathway in LT-deficient mice. Furthermore, exogenous IL-22 expression rescued LTβR deficient mice. IL-22 producing ILCs were predominantly located in lymphoid follicles in the colon, and interacted closely with dendritic cells. Finally, we find that an LT-driven positive feedback loop controls IL-22 production by RORγt+ ILCs via LTβR signaling in dendritic cells. Altogether, we show that LTβR signaling in gut lymphoid follicles regulates IL-22 production by ILCs in response to mucosal pathogen challenge.

Absence of Nkx2-3 Homeodomain Transcription Factor Reprograms the Endothelial Addressin Preference for Lymphocyte Homing in Peyer’s Patches

“…This is in line with previous reports showing the importance of LTbR signaling in HEV differentiation and function in wild-type mice (30). Possible sources of the non-T/non-B LT signals in the Nkx2-3 2/2 3 Rag1 2/2 double mutants are CD11c + dendritic cells that have been shown to influence HEV development and maintenance (32) and also retinoic acid-related orphan receptor gt + innate lymphoid cells, which have been reported to express LT (33). Germinal center-associated follicular dendritic cells continue to express MAdCAM-1 in Nkx2-3 mutant PPs, despite Nkx2-3 mRNA being expressed in stromal cells in normal mice, underlining the endothelial cell type-specific effect of the Nkx2-3 mutation.…”

Copycat innate lymphoid cells dampen gut inflammation

“…ILC3 maintain epithelial integrity and stimulate mucus secretion by releasing interleukin-22 (IL-22) and lymphotoxin [1,3,4], whereas Treg cells mitigate the pro-inflammatory activity of Teff cells by releasing transforming growth factor-β (TGF-β) and IL-10 [2]. Of note, these cytokines also stimulate B cell production of immunoglobulin A (IgA), a mucosal antibody class that controls commensal bacteria inhabiting the lumen of the gut [5].…”

Innate Lymphoid Cells: Immunoregulatory Cells of Mucosal Inflammation

“…For example, RORyt+ ILCs play an important role in defense against Citrobacter rodentium (24,25). During Citrobacter rodentium infection CD4+ LTi cells act as dominant source of early IL-22 release and this response is dependent on IL-23 as ablation of IL-23 impairs the innate immunity (25).…”

“…2). This early release of IL-22 by intestinal ILCs is induced by lymphotoxin (LT) during Citrobacter rodentium infection (25). Besides playing an important role in bacterial infection these cells are also important for symbiotic bacteria residing at mucosal surfaces (26).…”