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Antiviral Cytotoxic T Cells Cross-Reactively Recognize Disparate Peptide Determinants from Related Viruses but Ignore More Similar Self- and Foreign Determinants

Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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), MVE₁₇₈₅ (REHSGNEI) and MVE₁₉₇₁ (DEGEGRVI). The respective Tc cell populations cross-reactively lysed target cells pulsed with determinants from the MVE₁₇₈₅- and MVE₁₉₇₁-corresponding positions of six other flaviviruses, despite low sequence homology in some cases. Notably, anti-MVE₁₇₈₅ 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- 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.

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