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Paper Readig 01 Compartmentalized gut lymph node drainage dictatesadaptive immune responses  Qinchuan Wu, Wuhua Zhou, et al. Nature 2019 As we known，theintestinal immune system harbors the capabilities of tolerating foreignnutrients and the commensal microbiome, while excluding or eliminating ingestedpathogens. Failure of this balance leads to inflammatory bowel diseases, foodallergies and invasive gastrointestinal infections. Multiple immune mechanismsmaintain the tissue integrity, including balanced generation of effector T (TH)cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance topathogens and regulate excessive immune activation. The gut-draining lymphnodes (gLNs) are key sites for orchestrating adaptive immunity to luminalperturbations. In this paper, the authors showed that the gut lymph nodedrainage is compartmental, and each sections perform the different functions,different immune responses. They first imaged the gut lymphatic system using 3Dimaging exposed the lymphatic route of the intestine to gLNs via afferentlymphatic vessels in the mesentery. investigated the combination ofcompartmentalized absorption and drainage results in differential nutrientexposure in the gLNs by tracking the uptake of radiolabelled retinol afterfeeding(retinolis a lipid-soluble proxy and an immunomodulatory nutrient, andits uptake depends largely on packing into chylomicrons and lymphaticabsorption by the upper small intestine ) Most retinol was absorbed in theduodenum with a gradient along the intestine, and this was mirrored in the gLNsillustrating that the gLNs are exposed to region-specific lymph composition.After that, they analysed the transcriptomes of two major stromal cellpopulations, lymphatic endothelial cells (LECs) and fibroblastic reticularcells (FRCs), isolated from duodenal, ileal and caecal-colonic gLNs, PCAindicated that LECs and FRCs showed differential gene expression according tothe gut segment the gLNs drained. LECs from D-gLNs showed a distinct metabolicsignature indicative of elevated cholesterol and lipoprotein handling as wellas fatty acid utilization, probably driven by the lipid-rich lymph of theproximal small intestine. Also tested gut-segment-specific lymphatic drainageinfluenced the gene expression profiles of migratory dendritic cells, and next investigated CD4+ T cell fates correlated with migratory dendritic cell profiles orthe presence of microbiota and investigated the possible consequences ofanatomical segregation of T cell fates along the intestine, And the I-and C-gLNs are required for the generation of SFB specific TH17 cells, theproximal gLNs alone are necessary or sufficient for oral tolerance in a pTregcell-dependent process by surgical removal of the D-gLNs or the I- and C-gLNsfollowed by the induction of asthma suppression mediated by an oral antigen.Collectively,their datauncover a mechanism that the intestinal immune system simultaneously handlesregulatory versus pro-inflammatory responses, Theefficient drainage of dietary antigens into tolerance-promoting lymph nodesassociated with the proximal intestine which lymph nodes help to prevent foodallergies, and that duodenal infection and dysbiosis can alter the allergicoutcome. 02 The E3 Ubiquitin Ligase Asb2α in T Helper2 Cells Negatively Regulates Anti-tumor Immunity in Colorectal Cancer  CamilleA. Spinner, Isabelle Lamsoul, et al.. Cancer immunology research. 2019The escape of cancer cells from hostimmunosurveillance involves a shift in immune responses,including an imbalance inTh1 and Th2cells. A Th1-dominated immune response predicts positive outcome in colorectalcancer (CRC). The E3 ubiquitin ligase Asb2α is expressed in Th2 cells, but itsroles in T cell maturation and cancer are unclear. In this paper, the author provideevidence that the Th2 master regulator Gata3 induces Asb2. Loss of Asb2 did notaffect Th differentiation ex vivo, but reduced Il-4 production from Th2 cells. Firstly，theyconfirmed that Asb2α contributes to T cell maturation by quantitative RT-qPCR toevaluate the expression upon differentiation of wild-type naïve CD4+ T cells invitro as well as Affymetrix gene chip data. Then Global mapping of H3K4me3 andH3K27me3 in naïve and CD4+ effector T cells indicated that H3K4me3 active markswere associated with Asb2 in Th2 cells and ChIP-seq analysis of Th2 masterregulator Gata3 in naïve and CD4+ T cells revealed Gata3 binding within theAsb2 locus in Th2 cells. Further Bioinformatics analysis suggested that Gata3positively modulates Asb2 expression by regulating histone methylation in Th2cells. Moreover, analysis of CRC patients sample suggested that high ASB2expression in human CRC is associated with shorter relapse-free survival. Usingthe Mx1-Cre;Asb2fl/fl mutant mouse model they found loss of Asb2 inhematopoietic cells inhibits colitis-associated CRC in mice, lacking Asb2display markedly reduced Th2 and Treg together with enhanced Th1, Th17 and CTLresponse. Ex vivo generation of Th2 cells from naïve CD4+ cells deletion Asb2impedes Th2 response . at last, to evaluate the role of IFN-γ in the reducedtumor progression in cKO mice, anti-IFN-γ neutralizing antibodies were injectedto cKO mice revealed that enhanced expression of IFN-γ upon loss of Asb2 in Th2cells suppresses CRC progression in mice. Altogether, their data suggested thatAsb2α is an unsuspected negative regulator of anti-tumor immune response inCRC, and demonstrate that Asb2α plays functional roles in Th2 cells. END |
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