Autoimmune diabetes as a consequence of locally produced interleukin-2

Abstract

DURING cell differentiation in the thymus, self-reactive T cells can be generated. The majority of these seem to be deleted after intrathymic encounter with the relevant autoantigen¹. As all self antigens are unlikely to be present in the thymus, some autoreactive T cells may escape censorship. Here we study the fate of these cells using transgenic mice expressing the class I molecule H–2K^b(K^b) in the insulin-producing β -cells of the pancreas^2,3. These mice were crossed with mice transgenic for genes encoding a K^b-specific T-cell antigen receptor (TCR)⁴ which could be detected using a clonotype-specific monoclonal antibody⁵. Although T cells expressing the highest level of transgenic TCR were deleted intrathymi-cally in double-transgenic mice, K^b-specific T cells were detected in the periphery. These cells caused the rejection of K^b-expressing skin grafts, but ignored islet K^b antigens even after priming. But when double-transgenic mice were crossed with transgenic mice expressing the lymphokine interleukin-2 in the pancreatic β-cells⁶, there was a rapid onset of diabetes. These results indicate that autoreactive T cells that ignore self antigens may cause autoimmune diabetes when provided with exogenous 'help' in the form of interleukin-2.