Gut-specific eosinophils suppress IL-17 production by antagonizing IL-1 signaling

Prior to discovery of Toll-like receptors (TLR) in late 90s, immunology was dominated by concepts involving adaptive immune cells. However, for past 15 years it has become evident that innate immune cells of "all shapes and forms that exist out there" are equal partners with T and B cells and frequently provide instructions and actually control the magnitude and directions of adaptive immune response. For example, development of successful, next generation vaccines would require incorporation of these new concepts. 

It seems innate immune system is even more complex and unpredictable than T or B cells are. For instance, this week Journal of Experimental Medicine published new study wherein the authors reported that eosinophils, a cell population usually implicated in allergy and anti-helminth response, suppressed Th17 cells by antagonizing IL-1 signaling.

First, the authors observed that Th17 cells in ΔdblGATA-1 mice [which lack eosinophil-lineage cells] were significantly increased in the small intestine, but not in the spleen or mesenteric LNs (MLNs).

In vitro generation of Th17 cells were inhibited by presence of small intestinal eosinophils. 

Functional profiling revealed that small intestinal eosinophils secreted high amount of IL-1 receptor antagonist (IL-1Ra), which competes with IL-1β for receptor binding (IL-1 signaling is involved in Th17 development).

Interestingly, eosinophils were the major producers of IL-1Ra in small intestine, since no IL-1Ra was detected in small intestinal tissue from ΔdblGATA-1 mice. Of note, eosinophils from blood or bone marrow produced little or no IL-1Ra. 

In addition, the authors showed that small intestinal eosinophils derived from MyD88-KO or Germ Free (GF) mice produced WT-level IL-1Ra, suggesting its independence from gut flora or major TLR signaling.

Role of IL-1Ra in eosinophil mediated Th17 suppression in small intestine was confirmed in experiments with eosinophils derived from IL-1Ra-KO mice.   

In summary, this study showed that small intestine harbors specialized eosinophils secreting high amount of IL-1Ra and suppressing steady-state development of Th17. 

David Usharauli

Species-specific microbial attachment to host epithelial cells determines gut IL-17 induction

Gut microbes drive maturation of host's immune system. Not every microbe is able to do it, however. So what microbial qualities determines its impact on host?  

New paper in journal Cell has revealed a simple rule of thumb: microbes that could attach themselves to gut epithelial cells drove induction of local Th17 cells and IgA. Interestingly this microbial quality found to be species-specific. 

Initially, the authors showed that monocolonization of germ-free mice or rats with endogenous segmented filamentous bacteria  (mouse-SFB and rat-SFB) induced Th17 cells in a species-specific manner (mouse data are shown here ).   

Ex vivo stimulation of lamina propria cells with autoclaved fecal antigens (A/C) showed that IL-17 secretion and IgA production were correlated with species-specific access to SFB antigens in the gut.

Additional experiments with WT microbes or microbes lacking adhesion molecules confirmed that epithelial adhesion determined IL-17/IgA production.

In summary, these results indicate that direct adhesion to gut epithelial cells is necessary pre-condition for local immune response induction. Mechanistically, this adhesion by microbes induces production of serum amyloid A (SAA) that primed local T cells for Th17 phenotype.

David Usharauli