Characterization of CXCL10 expression pattern in pancreatic islets of NOD mice and type 1 diabetic patients: a new role for alpha-cells in T-lymphocytes recruitment

Background: in type 1 diabetes (T1D), the chemokine CXCL10 recruits autoreactive T-lymphocytes in pancreatic islets, contributing to beta-cells destruction. CXCL10 is expressed by murine and human pancreatic islets in autoimmune diabetes, however the specific expression pattern has not been elucidated yet. Our purpose was to clarify pancreatic CXCL10 expression, both in NOD mice and T1D patients.

Methods: we analyzed pancreatic sections from 4 C57Bl/6J 8 weeks(w), 3 C57Bl/6J 15-20 w, 4 NOD-SCID 2-3 w, 4 NOD normoglycemic (NG) 22 w, 4 NOD recent diabetic (RD) 12-21 w old mice, 6 new-onset T1D patients participating in Diabetes Virus Detection (DiViD) study and 3 non-diabetic organ donors from European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). Immunofluorescence, confocal microscopy analysis and colocalization analysis insulin-CXCL10 (INS-CXCL10) and glucagon-CXCL10 (GCG-CXCL10) were performed. In mice, total CXCL10 positive volume was analyzed and normalized per islet volume; CXCL10 expression was correlated to lymphocytic infiltrates area.

Results: CXCL10 was expressed in pancreatic islets of NG and RD NOD but not in C57Bl/6J and NOD-SCID mice. GCG-CXCL10 colocalization rate (CR) was increased vs INS-CXCL10 (p<0.01) in RD NOD mice. INS-CXCL10 CR was similar between NG and RD NOD, GCG-CXCL10 was increased in RD vs NG NOD mice (p<0.001). CXCL10 positive volume was increased in RD vs NG NOD mice (p<0.01) and positively correlated to lymphocytic infiltrates area (r=0.44, p=0.02). CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. GCG-CXCL10 CR was increased vs INS-CXCL10 (p=0.003) and was similar in insulin-containing vs -deficient islets, suggesting that CXCL10 expression in alpha-cells is not driven by residual beta-cells. The preferential expression of CXCL10  by alpha-cells, both in NOD mice and T1D patients, suggests a new role for alpha-cells in the recruitment of autoreactive T-lymphocytes in pancreatic islets and a primary function in beta-cell damage.