Autoantigen-independent deletion of diabetogenic CD4(+) thymocytes by protective MHC class II molecules

Some MHC class II genes provide dominant resistance to certain autoimmune d iseases via mechanisms that remain unclear. We hare shown that thymocytes b earing a highly diabetogenic, I-A(g7)-restricted beta-cell-reactive TCR (4. 1-TCR) undergo negative selection in diabetes-resistant H-2(g7/x) mice by e ngaging several different antidiabetogenic MHC class II molecules on thymic (but not peripheral) hemopoietic cells, independently of endogenous supera ntigens. Here rw have investigated 1 whether this TCR can also engage prote ctive MHC class II molecules (I-Ab) on cortical thymic epithelial cells in the absence of diabetogenic (I-A(g7)) molecules, and 2) whether deletion of 4.1-CD4(+) thymocytes in I-A(b)-expressing mice might result from the abil ity of I-A(b) molecules to present the target p-cell autoantigen of the 4.1 -TCR. We show that, unlike I-A(g7) molecules, I-A(b) molecules can restrict neither the positive selection of 4.1-CD4(+) thymocytes in the thymic cort ex nor the presentation of their target autoantigen in the periphery. Delet ion of 4.1-CD4(+) thymocytes by I-A(b) molecules in the thymic medulla, how ever, is a peptide-specific process, since it can be triggered by hemopoiet ic cells expressing heterogeneous peptide/I-A(b) complexes, but not by hemo poietic cells expressing single peptide/I-A(b) complexes. Thus, unlike MHC- autoreactive or alloreactive TCRs, which can engage deleting MHC molecules in the thymic cortex, thymic medulla, and peripheral APCs, the 4.1-TCR can only engage deleting MHC molecules (I-A(b)) in the thymic medulla, We there fore conclude that this form of RHC-induced protection from diabetes is bas ed on the presentation of an anatomically restricted, nonautoantigenic pept ide to highly diabetogenic thymocytes.