Differential action of TIGIT on islet and peripheral nerve autoimmunity in the NOD mouse

Abstract

We previously demonstrated that the abrogation of the ICOS pathway prevents type 1 diabetes development in the Non Obese Diabetic (NOD) mouse, but results in a CD4+ T-cell dependent autoimmune neuromyopathy in aged mice. Pancreatic islet infiltrates in conventional NOD mice and neuromuscular infiltrates in Icosl-/- NOD mice have in common that they exhibit a strong enrichment in CD4+TIGIT+ T-cells, whilst TIGIT expression in the peripheral CD4+ T-cells is limited to the CD4+FoxP3+ T-cell population. When deleting Tigit on the NOD background, diabetes incidence was found increased. Peripheral CD4+CD226+ effector T-cells exhibited an increased frequency of IL-17 producing CD4+CD226+RORgt+ T-cells versus a decreased frequency of IFN{gamma}-producing CD4+CD226+Tbet+ T-cells. ICOS is expressed in both CD4+FoxP3+ and CD4+CD226+ splenic T-cell subsets. Icosl deletion leads to a decrease of CD4+FoxP3+ cells, with decrease of PD1 but increase of ICOS and CCRX3. Also in the Icosl-/- model, CD4+CD226+ T-cells are decreased by Tigit deletion, and showed an increase of CD4+CD226+RORgt+ T-cells and a decrease of CD4+CD226+Tbet+ T-cells. However, deletion of Tigit in aged Icosl-/-NOD mice population did not increase the incidence of the autoimmune neuromyopathy observed in Icosl-/-NOD mice. Interestingly, the upregulation of CD4+CD226+RORgt+ T-cells was partly rescued. We conclude from our study that both Icosl and Tigit deletions on the NOD background lead to a shift between the ratio of IFN{gamma} and IL-17-producing CD4+CD226+ effector cells. The ICOS-dependent neuromyopathy development remains dominant and is not further altered in the absence of TIGIT. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/568543v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@de7ba4org.highwire.dtl.DTLVardef@8756b0org.highwire.dtl.DTLVardef@14c4a6borg.highwire.dtl.DTLVardef@1a9cd02_HPS_FORMAT_FIGEXP M_FIG C_FIG