# The XCL1/XCR1 axis is upregulated in type 1 diabetes and aggravates its pathogenesis

## TL;DR

This study shows that the XCL1/XCR1 chemokine axis is involved in type 1 diabetes and that blocking it reduces disease severity in mice.

## Contribution

The study identifies XCL1/XCR1 as a novel therapeutic target for type 1 diabetes.

## Key findings

- XCL1/XCR1 is upregulated in T1D patients and autoantibody-positive individuals.
- XCL1 deficiency reduces T1D incidence by limiting XCR1+ DC infiltration and T cell activation.
- Blocking XCL1/XCR1 may offer a new treatment for T1D.

## Abstract

Type 1 diabetes (T1D) is precipitated by the autoimmune destruction of the insulin-producing β cells in the pancreatic islets of Langerhans. Chemokines have been identified as major conductors of islet infiltration by autoaggressive leukocytes, including antigen-presenting cells and islet autoantigen–specific T cells. We have previously generated a road map of gene expression in the islet microenvironment during T1D in a mouse model and found that most of the chemokine axes are chronically upregulated during T1D. The XCL1/XCR1 chemokine axis is of particular interest, since XCR1 is exclusively expressed on conventional DCs type 1 (cDC1) that excel by their high capacity for T cell activation. Here, we demonstrate that cDC1-expressing XCR1 are present in and around the islets of patients with T1D and of individuals with islet autoantibody positivity. Furthermore, we show that XCL1 plays an important role in the attraction of highly potent DCs expressing XCR1 to the islets in an inducible mouse model for T1D. XCL1-deficient mice display a diminished infiltration of XCR1+ cDC1 and, subsequently, a reduced magnitude and activity of islet autoantigen–specific T cells, resulting in a profound decrease in T1D incidence. Interference with the XCL1/XCR1 chemokine axis might constitute a novel therapy for T1D.

The chemokine axis XCL1/XCR1 is expressed in type 1 diabetes patients. A interference with this axis ameliorates type 1 diabetes in a mouse model.