Interleukin-9 promotes early mast cell-mediated expulsion of Strongyloides ratti but is dispensable for generation of protective memory

Abstract

IL-9 is a cytokine with pleiotropic function that mediates allergic inflammation and immunity to intestinal helminth parasites. Accumulating evidence suggests that IL-9 acts via both, initiation and regulation of adaptive immune responses and direct activation of intestinal effector pathways. Here we use IL-9 receptor deficient mice on BALB/c and C57BL/6 genetic background to dissect effector and regulatory functions of IL-9 during infection with the parasitic nematode Strongyloides ratti. IL-9 receptor-deficient mice displayed increased intestinal parasite burden and prolonged infection irrespective of the genetic background of the mice. Increased parasite burden was correlated to a reciprocally reduced early degranulation of mucosal mast cells, reduced intestinal IL-13 expression and caused by IL-9 receptor deficiency on hematopoietic cells. We observed additional significant changes in the adaptive immune response to S. ratti infection in the absence of the IL-9 receptor that depended on the mouse strain. However, the generation of protective memory to a second infection was intact in IL-9 receptor-deficient mice, irrespective of the genetic background. In summary, our results support a central role for IL-9 as an early mast cell activating effector cytokine during intestinal helminth infection while non-redundant functions in the initiation and amplification of adaptive immune responses were not apparent.

Basophils are dispensable for the establishment of protective adaptive immunity against primary and challenge infection with the intestinal helminth parasite Strongyloides ratti

“…ratti antigen (Fig 2A) or anti-CD3 mAb (Fig 2B) elicited secretion of Th2 associated cytokines such as IL-13, IL-4 and IL-5 in basophil-deficient and basophil-competent mice to the same extent. Production of IL-9 and IL-3, cytokines that are central in immunity to Strongyloides [19, 20], were unchanged by basophil deficiency. Finally, the production of IL-10 that may, according to context and parasite species, contribute to protection or immune evasion [21] was not modulated by basophil deficiency.…”

“…In sharp contrast, deficiency of mast cells resulted in prolonged infection to more than 20 weeks pointing out the non-redundant function of IL-9 activated mast cells as intestinal effectors during S . ratti infection [4, 20].…”

Crosstalk between the Producers and Immune Targets of IL-9

“…MCs are a major target group of IL-9 as they express significant levels of IL-9R ( 42 ). Hematopoietic cells including activated Tregs, Th9, ILC2, and NKT cells are the main sources of IL-9 for in situ accumulation of MCs ( 19 83 84 ) ( Fig 2 ). Recent in vivo evidence suggests that IL-9 serves as a chemoattractant to recruit activated MCs.…”

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“…(ii) IL-33, in concert with other alarmin cytokines such as IL-25 was shown to mediate expansion of ILC2s [42][43][44] that are the dominant source of innate IL-9 [21,38]. (iii) IL-9 promotes mucosal mast cell activation [14] and (v) activated mast cells mediate S. ratti expulsion from the intestine [12].…”

“…Lung, spleen and peritoneal cavity cells (PECs) were isolated and single cell suspension prepared. Single cells were isolated from the lung as described before [14]. For surface staining, 3-5 x 10 6 cells were stained for 25 minutes at 4˚C with Biotin-labeled (lineage cocktail) targeting mouse CD11b (clone M1/70), CD8 (clone 53-6.7), CD19 (clone 6D5), CD11c (clone N418), CD3 (clone 17A2), TCRβ (clone H57-97), TCRγδ (Clone GL3), Gr-1 (clone RB-8C5), CD5 (clone 53-7.3), CD49b (clone DX5), TER-199 (clone TER-119) and NK1.1 (clone PK136), BV510-labeled anti-mouse CD4 antibody (clone RM4-5), AF700-labeled anti-mouse CD45 antibody (clone 30-F11), PE-Cy7-labeled anti-mouse CD90.2 antibody (Clone30-H12) and BV421-labeled anti-mouse CD127 antibody (clone A7R34).…”