Estimates of cytotoxic T-lymphocyte precursor frequencies against HLA class I antigens in responder-stimulator pairs with a negative mixed lymphocyte culture reaction.

Functional studies of helper and cytotoxic T cells in families with recombinant HLA haplotypes have played a crucial role in the early studies of the HLA chromosomal region. It has been shown that for the generation of CTLs directed against HLA-A or -B antigen differences an additional difference in the HLA-D region between responder and stimulator cells was a prerequisite. We have re-examined in a sensitive limiting dilution assay the possibility of generating CTL against HLA class I antigens in responder-stimulator pairs with a negative MLC reaction of two recombinant families (differing in one or two HLA class I antigens but identical in class II antigens) and two pairs of unrelated individuals. In all cases we could detect low but definitely measurable CTL activity (8-15 CTL precursors in 10(6) PBMCs) directed against the mismatched class I HLA antigen(s). We conclude that mismatches in class I HLA antigens in MLC nonreactive responder-stimulator pairs can induce generation of allospecific CTLs. This has implications in allogeneic bone marrow transplantation with HLA-matched unrelated donors; i.e., in the case of an HLA-A,B,DR matched donor a low donor CTLpf against the recipient may be an indication of a serologically not-detected class I HLA "subtype" incompatibility which might cause graft-versus-host disease.