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

Abstract

SummaryWe 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 inIcosl-/-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 deletingTigiton 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-cellsversusa decreased frequency of IFNγ-producing CD4+CD226+Tbet+T-cells.ICOS is expressed in both CD4+FoxP3+and CD4+CD226+splenic T-cell subsets.Icosldeletion leads to a decrease of CD4+FoxP3+cells, with decrease of PD1 but increase of ICOS and CCRX3. Also in theIcosl-/-model, CD4+CD226+T-cells are decreased byTigitdeletion, and showed an increase of CD4+CD226+RORgt+T-cells and a decrease of CD4+CD226+Tbet+T-cells.However, deletion ofTigitin agedIcosl-/-NOD mice population did not increase the incidence of the autoimmune neuromyopathy observed inIcosl-/-NOD mice. Interestingly, the upregulation of CD4+CD226+RORgt+T-cells was partly rescued.We conclude from our study that bothIcoslandTigitdeletions on the NOD background lead to a shift between the ratio of IFNγ 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.