Regulatory function of human CD4 + cytolytic T lymphocytes

Abstract

Allograft rejection is mediated by both CD4 + and CD8 + T cells. The lytic function of the classic CD8 + cytolytic T lymphocytes (CTL) occurs through recognition of allogeneic major histocompatibility complex (MHC) class I on the surface of the graft. CD4 + CTL recognize MHC class II through a direct recognition pathway or an indirect pathway where MHC peptides are presented 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 regulate CD8 + CTL by recognition of donor MHC peptides presented by self MHC class II expressed on CD8 + T cells. To define the role of CD4 + CTL in allograft outcome we used a CD4 + CTL that is MHC class II restricted, recognizing human leucocyte antigen (HLA)-A1 and HLA-B8 peptides in the context of HLA-DR4. This line (MDSxA1/B8) will lyse DR4 + B lymphoblastoid cells (LCL) pulsed with HLA-A1/B8 peptides (amino acids 60–84 of the α 1 domain 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-DR4. These clones must process and present the MHC class I peptides for recognition and lysis to occur. These results suggest a possible mechanism to explain allograft tolerance. Lytic CD4 + T cells, that recognize donor HLA peptides through an indirect antigen presentation pathway, down-regulate donor-specific CTL through peptide-specific lysis resulting in graft tolerance.