Innate help to Tregs in the gut

New study in @Nature indicates gut #ILC3 (type 3 innate lymphoid cells) produce IL-2 for #FOXP3+ Tregs. Is it relevant? lets discuss it. #Immunology #tolerance #microbiota https://t.co/iziPJb09Zy

— David Usharauli (@3DiMMUNE) April 3, 2019

2. Interestingly, the #frequency of IL-2-producing ILC3s was depended on the presence of #microbiota. Specifically, the authors showed that #cytokine IL-1 produced by #macrophages signaled ILC3 to produce IL-2. #MyD88 was involved (it is needed to produce IL-1 anyway). pic.twitter.com/dGb66Pqnwt

— David Usharauli (@3DiMMUNE) April 3, 2019

4. However, it is clear that IL-2 inactivation in NCR1-cre mouse is not clean and some ILC3 retain a capacity to secrete IL-2 (otherwise there should not be any IL-2+ ILC3 in this graph). pic.twitter.com/Zwbz2dDP3n

— David Usharauli (@3DiMMUNE) April 3, 2019

6. To complete the story the authors showed that individuals with #Crohn's disease harbor fewer ILC3 that produce IL-2 to feed Tregs in the small intestine suggesting that one reason why CDs could generate #inflammatory condition. pic.twitter.com/k2LN2LeMFe

— David Usharauli (@3DiMMUNE) April 3, 2019

in summary, this study showed that ILC3-produced IL-2 could support Treg functionality in the small intestine. This cooperation between ILC3 and Tregs appears to be antigen-nonspecific as mice with ILC3 deficient for MHCII does not show changes in Tregs. 1/3

— David Usharauli (@3DiMMUNE) April 3, 2019

I like to point out that out of so many figures only 1 figure shows a reduction of Treg numbers in the small intestine that supports the authors' claims of the role of ILC3-derived IL-2 in Treg homeostasis, the rest are shown as % (not optimal) or does not support claims. 3/3

— David Usharauli (@3DiMMUNE) April 3, 2019

Newborns' resistance to pneumonia is driven by acquired microbiota

This week Science Translational Medicine published new study that showed that in newborn mice resistance to pneumonia is driven by neonatally acquired microbiota. It revealed how antibiotic therapy given to mothers near time of delivery could alter and weaken baby's defenses against airway pathogens.

Newborn mice derived from germ-free or from antibiotic-exposed pregnant mice display increased susceptibility to Streptococcus pneumoniae serotype 19A-induced pneumonia that could be reversed by microflora.

Application of epithelial-focused cytokine IL-22 had similar effect on reversing newborn mice susceptibility to pneumonia.

In the lungs of newborn mice, majority of IL-22 is made by RORgt+ group 3 innate lymphoid cells (ILC3).

Antibiotic therapy of pregnant mice reduced IL-22+ ILC3 population in the newborn lungs that could be reversed by microflora.

Moreover, depletion of endogenous ILC3 increased host's susceptibility to pneumonia that could be reversed by adoptive transfer of WT ILC3.

In summary, this study showed that antibiotic therapy of pregnant females at the time of delivery could profoundly affect newborns' ability to mount proper defense against airway pathogens by depleting microflora and disrupting microflora → ILC3 → IL-22 axis.


David Usharauli

Group 3 innate lymphoid cells express RET and respond to glia-neuron network

Few days back journal Nature reported very interesting study from Portugal. In there, the authors showed that intestine glial cells (which are neuron-satellites expressing the glial fibrillary acidic protein (GFAP) signal local innate ILC3 cells via tyrosine kinase receptor RET.

First, they showed that ILC3 express RET that receives signals from glial-derived neurotrophic factor family ligands.

Second, mice lacking RET specifically in ILC3 cells, Rorgt-CreRet fl/fl (RetΔ), displayed marked reduction of IL-22, a cytokine involved in epithelial homeostasis.

Third, RetΔ mice showed heightened T cell-independent susceptibility to chemical [DSS]-induced colitis and to intestinal infection with the attaching and effacing bacteria Citrobacter rodentium.

Fourth, it showed that glial cells (RFP, red) are located in close proximity to ILC3 cells (GFP, green).

Fifth, mice lacking MyD88 specifically in glial cells, Gfap-CreMyd88Δ mice, also displayed heightened susceptibility to DSS colitis, indicating cross-talk between TLR signaling, glial-derived RET ligands and IL-22 produced by ILC3.

In summary, this study revealed existence of a complex network of neuro-glial-immune interactions that result in optimal defense against intestinal irritation. 

David Usharauli

Pregnancy-associated microbiota modules newborn's group 3 innate lymphoid cells (ILC3)

It is common believe that newborns are born sterile and their immune system undergoes changes at post-natal period in response to their own microbial exposure.

However, new study in Science challenges this concept by showing that mother's microbiota during pregnancy has permanent impact on offspring's postnatal innate immune system. 

To distinguish effects of maternal vs. neonatal microbiota on neonate's immune system, the authors used a "system in which pregnant dams are transiently colonized with genetically engineered Escherichia coli HA107", a E. coli strain that does not persist in the host and "pregnant dams become germ-free again before term and naturally deliver germ-free pups". Compared to control, microbiota-nil pregnant females, offsprings derived from temporally colonized pregnant females contained more IL-22 producing intestinal ILC3 (there was no effect on T or B cell numbers).

Maternal microbiota effect on newborn's ILC3 numbers could be reproduced by injecting germ-free pregnant females with serum (IgG) derived from HA107 colonized females (though it is not clear whether microbiota-specific IgG or any random IgG could produce the same effect).

Similarly, maternal microbiota effect on newborn's ILC3 numbers was lost in pregnant females lacking B cells (Ig_H^-/-).

In summary, this study suggests that pregnancy-associated microbiota does have an independent effect on maturation of newborn's innate immune system, at least via maternally-derived antibodies.

David Usharauli