A. Developing thymocytes are selected on the cortical epithelial cells with T1D-linked MHC II molecules. In the medulla, cross-reactive autoreactive cells encountering mismatched MHC II molecules undergo negative selection. Noncross- reactive autoreactive cells are unable to interact with mismatched MHC and fail to undergo negative selection and escape to the periphery.
B. In the spleen and lymph nodes, donor-type Treg cells interact with both donor- and host-type DCs to confer tolerogenic phenotypes on DCs. Residual crossreactive autoreactive T cells (which can interact with donor-type DC, as well as host-type DC) and non-cross-reactive T cells (which can only interact with hosttype DC) are tolerized.
C. Autoreactive B cells enter the spleen, and are tolerized through several proposed mechanisms. 1) Autoreactive B cells in competition for survival factors such as BAFF fail to outcompete non-autoreactive donorand host-type B cells. 2) Autoreactive B cells that manage to survive to maturity fail to find T cell help as the T cells were either deleted in the thymus or spleen, or were rendered anergic after encountering donor-Treg and tolerogenic DCs.
Figure 1: Model for re-establishing central and peripheral tolerance in autoimmune NOD mice after induction of mixed Chimerism with bone marrow transplants from MHC-mismatched donors.