Self-restricted primary human histocompatibility leukocyte antigen (HLA)-specific cytotoxic T lymphocytes

The specificity of self MHC-restricted T cells responding to peptide fragments of processed antigen has been well characterized. However, the means by which alloreactive T lymphocytes recognize MHC alloantigen remain poorly understood. We now provide evidence that the recognition of class I human leukocyte antigen (HLA) alloantigen by alloreactive cytotoxic T lymphocytes (CTL) induced in primary mixed lymphocyte cultures is class I HLA-restricted to a great extent. This is shown by the 'split-well' limiting dilution assay using third party target cells bearing a stimulating class I HLA alloantigen either in (i) the presence or (ii) the absence of class I HLA antigen(s) which is shared with the responder. Alloreactive CTL were found which recognize stimulator class I HLA alloantigen on the first but not on the second type of target cells. The results show that, in contrast to the traditional view, a large proportion of the alloreactive CTL against class I HLA alloantigen generated in primary mixed lymphocyte cultures is self class I HLA-restricted.