Antiviral cytotoxic T cells cross-reactively recognize disparate peptide determinants from related viruses but ignore more similar self- and foreign determinants.
We have investigated the reactivities of cytotoxic T (Tc) cells against the two immunodominant, H-2K(k)-restricted determinants from the FLAVIVIRUS: Murray Valley encephalitis virus (MVE), MVE(1785) (REHSGNEI) and MVE(1971) (DEGEGRVI). The respective Tc cell populations cross-reactively lysed target cells pulsed with determinants from the MVE(1785)- and MVE(1971)-corresponding positions of six other flaviviruses, despite low sequence homology in some cases. Notably, anti-MVE(1785) Tc cells recognized a determinant (TDGEERVI) that shares with the determinant used for stimulation only the carboxyl-terminal amino acid residue, one of two H-2K(k) anchor residues. These reactivity patterns were also observed in peptide-dependent IFN-gamma production and the requirements for in vitro restimulation of memory Tc cells. However, the broad cross-reactivity appeared to be limited to flavivirus-derived determinants, as none of a range of determinants from endogenous mouse-derived sequences, similar to the MVE-determinants, were recognized. Neither were cells infected with a number of unrelated viruses recognized. These results raise the paradox that virus-immune Tc cell responses, which are mostly directed against only a few "immunodominant" viral determinants, are remarkably peptide cross-reactive.
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
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Regner
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Lobigs
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Blanden
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Milburn
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Müllbacher
D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D003716:Dengue Virus / Q000276:immunology; D018068:Encephalitis Virus, Murray Valley / Q000235:genetics / Q000276:immunology; D018349:Encephalitis Viruses, Japanese / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005416:Flavivirus / Q000276:immunology*; D006183:H-2 Antigens / Q000378:metabolism; D016056:Immunodominant Epitopes / Q000378:metabolism*; D007156:Immunologic Memory; D051379:Mice; D008808:Mice, Inbred CBA; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014407:Tumor Cells, Cultured; D014902:West Nile virus / Q000276:immunology; D015005:Yellow fever virus / Q000276:immunology
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D016056:Immunodominant Epitopes; D009842:Oligopeptides