Minor lymphocyte stimulating (Mls) gene products in mice influence their genetic resistance or susceptibility to induction of autoimmune encephalomyelitis.

The role of the major histocompatibility complex (MHC) gene products in the genetics of experimental autoimmune encephalomyelitis (EAE) is well established. Here we demonstrate how non-MHC gene products, stimulatory to T cells specific to myelin basic protein (MBP), can affect the MHC control in determining genetic susceptibility or resistance to induction of EAE. I-As-restricted MBP-specific T cells derived from SJL/J mice are shown to cross-react with Mls-2a gene products. The Mls-2a gene product expressed by (SJL/J X BALB/c)F1 mice tolerize T cells recognizing I-As/MBP and favor the development of I-Es/d-restricted MBP-specific T cells mediating EAE in the (SJL/J x BALB/c)F1 mice. These I-Es/d/MBP-specific T cells, cross-reactive with Mls-1a, and the I-As/MBP-specific T cells, cross-reactive with Mls-2a gene products, are both eliminated by self tolerance mechanisms in the H-2-matched (SJL/J X DBA/2)F1 mice, expressing Mls-1a2a gene products, and thereby confer genetic resistance to EAE on the (SJL/J X DBA/2)F1 mice bearing EAE-permissive MHC alleles. These results reflect a developmental selection of a T cell repertoire to the self antigen MBP, imposed by self tolerance to self Mls gene products, which affect the genetic susceptibility to EAE. These studies also demonstrate that self tolerance to Mls gene products can strengthen the tolerance to organ-specific self antigens such as MBP, which may not be expressed or which are absent in the thymus at the time of thymic selection.