T cell expression of MHC class II glycoproteins: Presentation of the self-peptide rat myelin basic protein induces tolerance in the Lewis rat model of EAE.

摘要

During inflammation, T-helper cells express class II MHC glycoproteins and present antigens to other T cells. The first aim of this thesis was to assess the ability of partially agonistic self-antigens to generate a T cell APC (T-APC) phenotype and regulate the reciprocal activation of professional antigen presenting cells (APC). For this purpose, rat (R) myelin basic protein (MBP) was used to stimulate a rat CD4-CD8- T cell clone (3H3). RMBP induced T cell expression of MHC class II, however, RMBP did not increase expression of B7 on 3H3 T cells or splenic APC. In cultures with the agonist guinea pig (GP) MBP, RMBP acted as a partial agonist/antagonist and inhibited T cell and APC expression of B7 without efficiently antagonizing GPMBP-induced I-A expression on T cells. Furthermore, 3H3 T cells cultured with RMBP and irradiated splenocytes reduced the severity of EAE upon adoptive transfer into naive rat recipients subsequently challenged with GPMBP/CFA. These findings suggest a role for self-antigens in the generation of B7-deficient T-APC activity as a mechanism of tolerance in EAE.; Within the thymus, T cells are selected by recognition of partially agonistic self-peptides, and may therefore, have the ability to become T-APC. For this reason, the second aim assessed the ability of T cells to acquire MHC class II molecules during thymic development and pathogenic inflammation. Both rat and mouse thymic T cells expressed significant levels of MHC class II. Nonadherent rat thymocytes cultured overnight with RMBP presented to RMBP-specific responders and mediated the adoptive transfer of tolerance in naive rat recipients subsequently challenged with GPMBP/CFA. Derivation of mouse and rat chimeras revealed a significant amount of MHC class II molecules on thymic T cells was acquired from radioresistant host APC. Also, MBP-specific effector T cells isolated from CNS during EAE expressed MHC class II due, in part, to acquisition from APC. Overall, this study indicates that a significant source of MHC class II on T cells in vivo is acquired from neighboring APC. This mechanism may facilitate dissemination of MHC class II/peptide complexes among the T cell repertoire and may contribute to both central and peripheral tolerance.