Role of the major histocompatibility complex in targeting effector T cells into a site of virus infection

Bone marrow radiation chimeras have been used as virus-infected, cyclophosphamide-suppressed recipients to analyze the major histocompatibility complex (MHC) restriction constraints on the adoptive transfer of lymphocytic choriomeningitis by immune T cells. The basic protocol employed [(A X B)F1----(A X C)F1] chimeras, where A, B, C are different MHC haplotypes, and the establishment of appropriate chimerism was measured by the capacity of, for instance, the transferred A, T cells to generate MHC-restricted, virus-specific cytotoxic T lymphocytes (CTL) in the spleen of the [(A X B)F1----(B X C)F1] recipients. The experiments show quite clearly that maximal inflammatory process is only induced when donor bone marrow, irradiated recipient and transferred T cells share at least one MHC haplotype. Compatibility of the T cells and the radiation-resistant phenotype alone in, for instance, transfer of C immune lymphocytes into [(A X B)F1----(B X C)F1] recipients produced little inflammation if the chimeras had been established for at least 10 weeks. These results are compatible with a model which proposes that the transferred T cells first replicate in MHC-compatible lymphoid tissue and are then targeted onto the appropriate MHC plus virus expressed on cells in the blood-cerebrospinal fluid (CSF) barrier. An alternative postulate, that all that is required for the development of inflammatory process is MHC-restricted T cell replication in lymphoid tissue, with subsequent nonspecific localization to the central nervous system (CNS), was explored by transferring B, immune T cells into [(A X B)F1----A] recipients. The finding was that H-2b effectors did not cause any meningitis in [H-2kXb F1----H-2k] recipients, though potent H-2b-restricted CTL were generated in the spleens of comparable chimeras. However, in the H-2k immune----[H-2kXbF1----H-2b] transfer there was evidence of moderate inflammation that was about 9 times less severe than that caused by the H-2b effectors in comparable recipients. This indicates that, for maximal inflammatory process to occur, the T cells must encounter MHC-compatible, virus-infected cells in the CNS, with the effect being absolute in one strain combination and partial in another. Possible mechanisms underlying this divergence are discussed.