Alloreactive cytotoxic T cells recognize MHC class I antigen without peptide specificity

In this report, experiments are described to differentiate between three potential models of class I MHC allorecognition, namely 1) recognition of peptide-free MHC, 2) peptide-MHC-specific recognition, and 3) peptide-MHC-nonspecific recognition. Using a nucleoprotein peptide (NPP) with a sequence derived from influenza virus nucleoprotein with high affinity for K^d class I MHC molecules, it is shown that target cells rapidly become lysable by K^d-NPP self-restricted cytotoxic T (Tc) cells, and retain sufficient K^d-NPP complexes for at least 72 h. K^d-specific alloreactive Tc cells at the clonal and polyclonal level do not show decreased lysis of K^d-bearing targets in the continuous long term (48 h) presence of NPP. K^d-stimulator cells modified with NPP are able to induce potent K^d-NPP-specific self-restricted Tc cells, however K^d-NPP stimulator cells do not generate K^d-NPP specific alloreactive Tc cells from CBA and B10.A (5R) mouse strains as tested by limiting dilution split clone experiments. Human cells infected with the vaccinia virus recombinant coding for the murine K^d class I MHC Ag can be lysed by murine K^d-specific alloreactive Tc cells. In addition the rate of reemergence of alloreactive and self-restricted Tc cell epitopes on virally infected target cells that had their cell-surface class I MHC Ag removed is identical. These results are consistent with model 3 namely that the majority of Tc precursor and effector cells recognize class I MHC Ag without peptide specificity.