Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice

Accumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response in hibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine s ecretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detect s IL-2, IL-4, and interferon-gamma (IFN-gamma) secretion in vitro at the si ngle-cell level. We showed that, whatever the age considered, IFN-gamma is predominantly secreted, and that no IL-4-secreting cells are detected in th e islets of male and female NOD mice. Spleen cells from 8-week-old female N OD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion by T cells from dia betic mice results from CD4 but not CD8 T cells in transfer experiments int o NOD/severe combined immunodeficient (SCID) recipients. These results sugg est that (i) detection of regulatory CD4 T cells in NOD mice is not paralle led by a Th2 response; (ii) beta cell destruction does not depend on a swit ch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not particip ate in induction of diabetes by secreting IFN-gamma.