Regulatory function of human CD4(+) cytolytic T lymphocytes

Allograft rejection is mediated by both CD4(+) and CD8(+) T cells. The lyti c function of the classic CD8(+) cytolytic T lymphocytes (CTL) occurs throu gh recognition of allogeneic major histocompatibility complex (MHC) class I on the surface of the graft. CD4(+) CTL recognize MHC class II through a d irect recognition pathway or an indirect pathway where MHC peptides are pre sented in the context of self MHC class II. Lytic CD4(+) cells may destroy graft tissue or, we hypothesize, the indirect CD4(+) T cell may down regula te CD8(+) CTL by recognition of donor MHC peptides presented by self MHC cl ass II expressed on CD8(+) T cells. To define the role of CD4(+) CTL in all ograft outcome we used a CD4(+) CTL that is MHC class II restricted, recogn izing human leucocyte antigen (HLA)-A1 and HLA-B8 peptides in the context o f HLA-DR4. This line (MDSxA1/B8) will lyse DR4(+) B lymphoblastoid cells (L CL) pulsed with HLA-A1/B8 peptides (amino acids 60-84 of the alpha(1) domai n of the MHC class I molecule). These T cells will also lyse peptide-pulsed antigen-specific T cell clones, both CD4(+) and CD8(+), that express HLA-D R4. These clones must process and present the MHC class I peptides for reco gnition and lysis to occur. These results suggest a possible mechanism to e xplain allograft tolerance. Lytic CD4(+) T cells, that recognize donor HLA peptides through an indirect antigen presentation pathway, down-regulate do nor-specific CTL through peptide-specific lysis resulting in graft toleranc e.