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

Both TNF-α and IL-1 are necessary for M. tuberculosis control

Both TNF-α and IL-1α are innate cytokines. For both cytokines there are FDA-approved biological drugs such as Humira® (TNF-α blocking) and Kineret® (IL-1RI blocking). Of note, anti-TNF-α, but not anti-IL-1RI blockers, carry specific FDA label regarding M. tuberculosis incidence as a drug side effect. 

So I was surprised to read new paper in journal Immunity where the authors showed that in mouse model of aerosol M. tuberculosis infection both TNF-α and IL-1 were required for efficient control of TB pathogen.

Of note, this article was under review for more than two years. I guess it took long time to convince editors to publish it. The study is based on analyses of bilateral bone marrow reconstituted knockout mice. Basically a descriptive study. I modified sequence of figures for clarity.  

In a first set of experiments the authors showed that mice deficient for IL-1α and IL-1β signaling on hematopoietic cells (DKO or IL-1RI KO) were highly susceptible to M. tuberculosis infection due to exaggerated, non-productive inflammatory response.

Follow up experiments with mice single deficient for IL-1α and IL-1β confirmed physiological significance of individual IL-1 molecules in host's defense against M. tuberculosis infection (the authors claim that IL-1β deficient hosts are less susceptible to M. tuberculosis infection, but overall survival trend is the same).

Significance of IL-1α in control of M. tuberculosis infection was supported by observation that transfer of stem cells expressing viral-encoded IL-1α under the control of CD11c promoter restored IL-1α KO host's resistance to M. tuberculosis infection (why the authors have not done the same experiment with IL-1β is unknown).

Next, the authors showed [or rather re-confirmed] that mice deficient for TNF-α signaling on hematopoietic as well as on non-hematopoinetic cells were susceptible for M. tuberculosis infection.

Additional experiments revealed that absence of signaling via both IL-1RI and TNF-R1 on non-hematopoietic cells [but not on hematopoietic cells] further diminished host's resistance against M. tuberculosis infection.

In summary, this study indicates that in mouse model of M. tuberculosis infection both TNF-α and IL-1 molecules play non-redundant role in host's defense. Interestingly, mice individually deficient for TNF-α or IL-1 signalling on hematopoinetic cells showed similar susceptible to M. tuberculosis infection (in contrast, only mice deficient for TNF-α, [but not IL-1] signalling on non-hematopoietic cells retain susceptibility to M. tuberculosis infection).

However, how these data fit with clinical studies with Humira® and Kineret® is another story altogether. Surprisingly, the authors failed to discuss it at all. That's a big problem.

David Usharauli