The study of self-tolerance using murine haemoglobin as a model self antigen

T cell tolerance to self proteins involves both thymic and peripheral mechanisms. We have used allotypic differences in murine haemoglobin (Hb) to study the development of tolerance to the abundantly expressed self-protein. In Hb beta s/H-2k mice, the response to Hb beta d is directed against Hb beta d (64-76) presented by I-Ek molecules. Using T cell hybridomas and clones specific for this epitope, we have demonstrated that Hb(64-76)/I-Ek complexes and present on antigen-presenting cells in all lymphoid organs including dendritic cells, B cells and macrophages. In the thymus, the presence of these complexes results in negative selection of transgenic T cells with high levels of Hb(64-76)/I-Ek-specific receptor. However, cells with intermediate levels of specific receptor escape negative selection and can be found in the periphery. Under normal circumstances these cells remain tolerant, but can be activated by mechanisms which increase the number of Hb(64-76)/I-Ek complexes.