Faculty Collaboration Database

CD11c⁺ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes. Front Immunol 2019;10:99

Date

02/16/2019

Pubmed ID

30766536

Pubmed Central ID

PMC6365440

DOI

10.3389/fimmu.2019.00099

Scopus ID

2-s2.0-85061573541 (requires institutional sign-in at Scopus site)   20 Citations

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.

Author List

Sandor AM, Lindsay RS, Dyjack N, Whitesell JC, Rios C, Bradley BJ, Haskins K, Serreze DV, Geurts AM, Chen YG, Seibold MA, Jacobelli J, Friedman RS

Authors

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CD11c Antigen
Diabetes Mellitus, Type 1
Female
Islets of Langerhans
Mice, Inbred NOD
Mice, Knockout
T-Lymphocytes