CYTOKINES RESTORE MHC CLASS-I COMPLEX-FORMATION AND CONTROL ANTIGEN PRESENTATION IN HUMAN CYTOMEGALOVIRUS-INFECTED CELLS

CD8(+) cytotoxic T cell (CTL) clones with specificity for defined mino r and major histocompatibility (H) antigens were used to monitor antig en presentation in human cytomegalovirus (HCMV)-infected skin fibrobla sts. At the immediate early stage of virus replication antigen present ation was intact, but was abolished during the early and late phase. L ack of CTL recognition was not selective for certain antigens but was associated with decreased steady state levels of nascent MHC class I c omplexes and unassembled MHC class I heavy chains, whereas free beta(2 )-microglobulin remained abundant. HCMV also affected the stability of both immature endoglycosidase H (Endo H)-sensitive and mature Endo H- resistant MHC class I molecules, suggesting that the virus interferes with antigen presentation at more than one step during maturation of t he MHC class I complex. The action of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) lifted the block of MHC clas s I complex formation by stimulating synthesis, assembly and stability of MHC class I molecules. This resulted in restored antigen presentat ion provided that cells were exposed to the factors before HCMV infect ion. Because few MHC molecules suffice for CTL recognition these cytok ines compensated for the negative viral effect on the antigen presenta tion function. Nevertheless, the viral interference with MHC class I c omplex formation was still active. The data imply that specific cytoki nes limit the immune evasion potential of HCMV from CD8(+) T lymphocyt e control.