Autoimmune diabetes as a consequence of locally produced interleukin-2.
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 autoantigen. 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-2Kb (Kb) in the insulin-producing beta-cells of the pancreas. These mice were crossed with mice transgenic for genes encoding a Kb-specific T-cell antigen receptor (TCR) which could be detected using a clonotype-specific monoclonal antibody. Although T cells expressing the highest level of transgenic TCR were deleted intrathymically in double-transgenic mice, Kb-specific T cells were detected in the periphery. These cells caused the rejection of Kb-expressing skin grafts, but ignored islet Kb antigens even after priming. But when double-transgenic mice were crossed with transgenic mice expressing the lymphokine interleukin-2 in the pancreatic beta-cells, 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.
Heath
W R
WR
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Allison
J
J
Hoffmann
M W
MW
Schönrich
G
G
Hämmerling
G
G
Arnold
B
B
Miller
J F
JF
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D015870:Gene Expression; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell