Dataset Information

CD11c⁺ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

ABSTRACT: Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that affects more than 19 million people with incidence increasing rapidly worldwide. For T cells to effectively drive T1D, they must first traffic to the islets and extravasate through the islet vasculature. Understanding the cues that lead to T cell entry into inflamed islets is important because diagnosed T1D patients already have established immune infiltration of their islets. Here we show that CD11c⁺ cells are a key mediator of T cell trafficking to infiltrated islets in non-obese diabetic (NOD) mice. Using intravital 2-photon islet imaging we show that T cell extravasation into the islets is an extended process, with T cells arresting in the islet vasculature in close proximity to perivascular CD11c⁺ cells. Antigen is not required for T cell trafficking to infiltrated islets, but T cell chemokine receptor signaling is necessary. Using RNAseq, we show that islet CD11c⁺ cells express over 20 different chemokines that bind chemokine receptors expressed on islet T cells. One highly expressed chemokine-receptor pair is CXCL16-CXCR6. However, NOD. CXCR6^-/- mice progressed normally to T1D and CXCR6 deficient T cells trafficked normally to the islets. Even with CXCR3 and CXCR6 dual deficiency, T cells trafficked to infiltrated islets. These data reinforce that chemokine receptor signaling is highly redundant for T cell trafficking to inflamed islets. Importantly, depletion of CD11c⁺ cells strongly inhibited T cell trafficking to infiltrated islets of NOD mice. We suggest that targeted depletion of CD11c⁺ cells associated with the islet vasculature may yield a therapeutic target to inhibit T cell trafficking to inflamed islets to prevent progression of T1D.

SUBMITTER: Sandor AM

PROVIDER: S-EPMC6365440 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD11c<sup>+</sup> Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

Sandor Adam M AM Lindsay Robin S RS Dyjack Nathan N Whitesell Jennifer C JC Rios Cydney C Bradley Brenda J BJ Haskins Kathryn K Serreze David V DV Geurts Aron M AM Chen Yi-Guang YG Seibold Max A MA Jacobelli Jordan J Friedman Rachel S RS

Frontiers in immunology 20190131

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that affects more than 19 million people with incidence increasing rapidly worldwide. For T cells to effectively drive T1D, they must first traffic to the islets and extravasate through the islet vasculature. Understanding the cues that lead to T cell entry into inflamed islets is important because diagnosed T1D patients already have established immune infiltration of their islets. Here we show that CD11c<sup>+</sup> cells are a key m ...[more]

PMID: 30766536

Similar Datasets

Project description:Aims/hypothesisNormal cellular prion protein (PrPC) is a conserved mammalian glycoprotein found on the outer plasma membrane leaflet through a glycophosphatidylinositol anchor. Although PrPC is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. The misfolded pathogenic isoform PrPSc (the scrapie form of PrP) is a causative agent of neurodegenerative prion diseases. The aim of this study is to evaluate PrPC localisation, expression and trafficking in pancreases from organ donors with and without type 1 diabetes and to infer PrPC function through studies on interacting protein partners.MethodsIn order to evaluate localisation and trafficking of PrPC in the human pancreas, 12 non-diabetic, 12 type 1 diabetic and 12 autoantibody-positive organ donor tissue samples were analysed using immunofluorescence analysis. Furthermore, total RNA was isolated from 29 non-diabetic, 29 type 1 diabetic and 24 autoantibody-positive donors to estimate PrPC expression in the human pancreas. Additionally, we performed PrPC-specific immunoblot analysis on total pancreatic protein from non-diabetic and type 1 diabetic organ donors to test whether changes in PrPC mRNA levels leads to a concomitant increase in PrPC protein levels in human pancreases.ResultsIn non-diabetic and type 1 diabetic pancreases (the latter displaying both insulin-positive [INS(+)] and -negative [INS(-)] islets), we found PrPC in islets co-registering with beta cells in all INS(+) islets and, strikingly, unexpected activation of PrPC in alpha cells within diabetic INS(-) islets. We found PrPC localised to the plasma membrane and endoplasmic reticulum (ER) but not the Golgi, defining two cellular pools and an unconventional protein trafficking mechanism bypassing the Golgi. We demonstrate PrPC co-registration with established protein partners, neural cell adhesion molecule 1 (NCAM1) and stress-inducible phosphoprotein 1 (STI1; encoded by STIP1) on the plasma membrane and ER, respectively, linking PrPC function with cyto-protection, signalling, differentiation and morphogenesis. We demonstrate that both PRNP (encoding PrPC) and STIP1 gene expression are dramatically altered in type 1 diabetic and autoantibody-positive pancreases.Conclusions/interpretationAs the first study to address PrPC expression in non-diabetic and type 1 diabetic human pancreas, we provide new insights for PrPC in the pathogenesis of type 1 diabetes. We evaluated the cell-type specific expression of PrPC in the human pancreas and discovered possible connections with potential interacting proteins that we speculate might address mechanisms relevant to the role of PrPC in the human pancreas.

Dataset Information

CD11c⁺ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

Publications

CD11c<sup>+</sup> Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

CD11c+ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

Publications

CD11c<sup>+</sup> Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD11c⁺ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.