Frontline: Self-peptides that bind with low affinity to the diabetes-associated I-Ag7 molecule readily induce T cell tolerance in non-obese diabetic mice

Abstract

Although non-obese diabetic (NOD) mice spontaneously develop T cell autoimmunity, it is not clear whether this phenomenon results from a defect in tolerance to self-Ag. Furthermore, as autoimmunity has been postulated to result from T cell responses directed toward self-peptides that bind with low affinity to NOD I-Ag7 MHC class 11 molecules, it is important to determine whether the expression of such pepticles induces tolerance. We have constructed NOD transgenic (Tg) mice expressing the Leishmania antigen receptor for C kinase (LACK) Ag in either the thymus or pancreatic β cells. We identified LACK peptides that were the targets of T cells in LACK-immunized NOD mice while binding to I-Ag7 with low affinity. While CD4+ T cells from NOD mice secreted IFN-γ, IL-4, IL-5 and IL-10 in response to LACK, those from LACK-expressing Tg mice secreted reduced levels of cytokines. Experiments using peptide/MHC multimers showed that LACK-expressing Tg mice exhibited self-reactive CD4+ T cells with impaired proliferation capabilities, Hence, even self-pepticles that bind to I-Ag7 with low affinity can induce tolerance in NOD mice. This result is important in light of the commonly held hypothesis that T cells reacting to peptides that bind to MHC with low affinity escape tolerance induction and cause autoimmunity.