IL-33 is a natural target of allergen proteases

IL-33 is a member of IL-1 family and requires proteolytic cleavage to form active form. It has already been linked to allergy manifestation. Now, new study in nature immunology expands on earlier observations to show that full-length non-active IL-33 (IL-33_FL) is a natural target of group of allergens with proteases activity.

In general, many known allergens display protease activity such as from fungi, mites, pollens, insects. Co-incubation of IL-33_FL with such allergen proteases in presence of innate lymphoid cells type II (ILC2) generated biologically-active smaller fragments and release of type II cytokines.

IL-33_FL is an intra-nuclear proto-chemokine found in epithelial and endothelial cells. So, how allergens get access to it? It requires cell damage to release IL-33_FL extra-cellularly. However, it is not clear if any allergen proteases can damage cells. At least one such allergen from fungus, Alternaria alternata (A. alternata) can damage cell and then cleave IL-33_FL.

Similar effects were seen in vivo using IL-33KO mice. In these mice, recruitment of eosinophils, a readout for IL-33-driven allergic response, were only observed when injected with pre-incubated IL-33_FL and A. alternata mixture.

In summary, these results suggest that allergen from A. alternata with protease activity can damage cells to release IL-33_FL and cleave it into biologically-active shorter peptides. However, this study did not show that other allergens can deliver similar double punch. Also, it is not clear how this innate mechanism translates to adaptive immune system to generate allergen-specific T cell and antibody responses.

posted by David Usharauli

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

Foxp3+ Tregs depletion activates anti-cancer immunity via eosinophils

Eosinophils are usually associated with atopic/allergic conditions. However, as with all cells involved in type II immune response, eosinophil's role in host's defense is not entirely clear.

This new paper in Nature Immunology provided evidence for eosinophil's anti-tumor function. The paper itself is quite "primitive", observation-type of research article. It belongs more to JEM, if you ask me. Still, it was accepted within 1 month of its submission to Nature Immunology. 

It appears that initial focus of this research was Foxp3+ Tregs. The authors showed that Foxp3⁺ Tregs depletion in Foxp3.LuciDTR-4 mice induced B16 melanoma rejection expressing nominal OVA antigen (MO4 tumor cells).

Surprisingly, this rejection of MO4 tumor was accompanied with selective eosinophil infiltration at tumor site.

Indeed, concomitant depletion of eosinphils with Siglec-F antibody significantly reduced anti-cancer effect seen with Foxp3⁺ Tregs depletion.

Additional experiments showed that anti-tumor effectiveness of adoptively transferred OVA-specific CD8 T cells were eosinophil dependent, though only in vitro IFN-γ + TNF-α activated, but not resting eosinophils could provide such help to CD8 T cells. Eosinophils alone were not effective.

The authors went on to show that activated eosinophils attracted CD8 T cells to tumor site and promoted normalization of tumor vasculature.

In summary, these results suggests that depletion of Foxp3⁺ Tregs activates eosinophils which in turn recruit CD8 T cells into tumor site leading to anti-tumor effect.

Now, why are eosinophils specifically involved in tumor protection in this model is not clear. What attracts eosinophils into tumors?

David Usharauli