Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Abstract

Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4+/CD8+ double-positive; 2) specific for an HLA class I–restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I–restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7–restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease–protective, minor H Ag–specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.