CD80 sequesters PDL1 on DC's surface and promotes T cell activation

An excellent study by Japanese scientists in @sciencemagazine reveals how co-#stimulatory molecule #CD80 sequestered co-#inhibitory molecule #PDL1 on the same DC's surface and thus promotes #Tcell #activation. #immunology #tolerance #Immunotherapy https://t.co/RcArRXV9XT

— David Usharauli (@3DiMMUNE) April 23, 2019

1. Initially, the authors made an #observation that unlike #macrophages #dendritic cells did not stain with soluble #PD1 molecule even though DCs expressed high levels of #PDL1 or #PDL2 (PD1 ligands). However, it was noted that DCs expressed a higher level of #CD80 too. pic.twitter.com/hH1CbYxt7L

— David Usharauli (@3DiMMUNE) April 23, 2019

3. Co-expression of #PDL1 with #CD80 [but not with CD86 or PDL2 with CD80 or another co-#stimulatory molecule CD86], on the same cell surface had a #functional consequence for OVA-specific T cell activation. It allowed more vigorous #activation and IL-2 production. pic.twitter.com/X0miudAspA

— David Usharauli (@3DiMMUNE) April 23, 2019

5. Here too, the combination of #PDL1 and #CD80 molecules that cannot interact with each other allowed more vigorous #inhibition of IL-2 production by T cells. #Mechanistically, it showed that 'liberated' PDL1 on DCs cross-interacts with PD1 on T cell and #inhibits it. pic.twitter.com/YxM6oskg3q

— David Usharauli (@3DiMMUNE) April 23, 2019

7. Similarly, mice expressing mutant PDL1 or CD80 molecules showed reduced inflammation in the brain [in #EAE #model] after priming with brain-specific antigens though the effect seems to be minimal. pic.twitter.com/P2fyIusL1M

— David Usharauli (@3DiMMUNE) April 23, 2019

It indicates PDL1 #sequestration by CD80 on DCs is not a major path that controls immunity in #physiological condition. The authors did not show if it undermines protection against #pathogens or #tolerance to gut #commensals.

— David Usharauli (@3DiMMUNE) April 23, 2019

Crohn's disease-like phenotype could be initiated by one gut microbe in genetically susceptible mice

1. The authors used doubly deficient Nod2−/−Cybb−/− [NADPH oxidase] (DKO) mice (genes thought to be altered in #Crohns). When fostered with Taconic dams, but not Jax dams, these DKO pups get spontaneous gut #inflammation after weaning (3 weeks post birth). pic.twitter.com/LdoBA8Dfao

— David Usharauli (@3DiMMUNE) April 20, 2019

3. using the #microbiota analysis tool (linear discriminant analysis
(LDA) effect size (#LEfSe) methodology) the author found that one particular microbiota species, M. schaedleri, showed 1349-fold enrichment in DKO mice but not in single KOs. pic.twitter.com/BzMUB63cGf

— David Usharauli (@3DiMMUNE) April 20, 2019

5. Time analysis showed that DKO pups fostered with Tac dams harbor M. schaedleri-specific IgA and IgG but only before weaning. These #antibody titers quickly decline post weaning that correlated with the onset of #CrohnsDisease-like phenotype. pic.twitter.com/elMRXdMdv3

— David Usharauli (@3DiMMUNE) April 20, 2019

In summary, this study showed that #spontaneous gut #inflammation could be recapitulated in mice doubly deficient for two specific genes, #NOD2 and #NADPH oxidase and exposed to specific gut #microbiota, Mucispirillum schaedleri.

— David Usharauli (@3DiMMUNE) April 20, 2019

So, here we have a complete model of spontaneous gut inflammation initiated by a particular gut microbe in a genetically susceptible host. Is it how #CrohnsDisease develops too in humans?

— David Usharauli (@3DiMMUNE) April 20, 2019

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