Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine, the site most commonly affected in inflammatory bowel disease. GPR15, an orphan G-protein coupled receptor, controlled the specific homing of T cells, particularly FOXP3+ regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression was modulated by gut microbiota and transforming growth factor-β1, but not by retinoic acid. GPR15-deficient mice were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus describe a T cell homing receptor for LILP and indicate that GPR15 plays a role in mucosal immune tolerance largely by regulating the influx of Tregs.

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.

Dendritic cells (DC) are antigen-presenting cells found in both lymphoid and nonlymphoid organs, including the brain (bDC) of Cd11c/eyfp transgenic C57BL/6 mice. Using an intranasal vesicular stomatitis virus infection, we demonstrated that EYFP + cells amass in areas associated with viral antigens, take on an activated morphology, and project their processes into infected neuronal tissue within the olfactory bulb. These bDC separated into three EYFP + CD45 + CD11b + populations, all but one being able to functionally promote both T lymphocyte proliferation and T H 1 cytokine production. One population was shown to emanate from the brain and a second population was peripherally derived. The third population was of indeterminate origin, being both radiosensitive and not replenished by donor bone marrow. Finally, each EYFP + population contained CD11b + CD103 + subpopulations and could be distinguished in terms of CD115, Gr-1, and Ly-6C expression, highlighting mucosal and monocyte-derived DC lineages.

No abstract

The large intestine is the site most commonly affected in inflammatory bowel diseases. However, the mechanism of T cell homing to the large intestine, which contributes to inflammation, had remained unclear. We show here that an orphan G-protein coupled receptor GPR15 controls the specific homing of T cells, particularly FOXP3+ regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression is promoted by gut microbiota and TGF-β1, but not by retinoic acid. GPR15-deficient mice had fewer Tregs in LILP and were prone to develop more severe inflammation in the large intestine, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus indicate that GPR15 is a T cell homing receptor for LILP and that GPR15 plays a key role in maintaining gut immune homeostasis, largely by regulating the influx of Tregs. Our study also demonstrates that adaptive immune responses in the gut are functionally compartmentalized through the differential requirements for T cell homing to the small and large bowel.

Dendritic cells (DC) are antigen presenting cells found in both lymphoid and non-lymphoid organs, including the brain (bDC) of Cd11c/eyfp transgenic C57Bl/6 mice. Using an intranasal vesicular stomatitis virus infection, we demonstrated that EYFP+ cells amass in areas associated with viral antigens, take on an activated morphology, and project their processes into infected neuronal tissue within the olfactory bulb. These bDC separated into three EYFP+ CD45+ CD11b+ populations: EYFP+ CD45int CD11bhi (P1), EYFP+ CD45hi CD11bhi (P2) and EYFP+ CD45hi CD11bint (P3) populations. All but the P1 population were able to functionally promote both T lymphocyte proliferation and TH1 cytokine production using an OT transgenic antigen presentation assay. Using radiation chimeras, P1 was shown to emanate from the brain, while P2 was established to be peripherally derived. Interestingly, the P3 population was of indeterminate origin, being both radiosensitive and not replenished by donor bone marrow. Finally, each EYFP+ population contained CD11b+ CD103+ sub-populations, and could be distinguished in terms of M-CSFR, Gr-1, and Ly-6C expression. Such phenotypic analysis point to P1 as an activated sub-population of microglia, while P2 was more typical of mucosal DC subsets and P3 appeared to be similar to monocyte-derived DC lineages.