Regulatory functions of human CD4(+) T cells recognizing allopeptides in the context of self-HLA class II.

Pretransplant blood transfusions sharing one human leukocyte antigen DR (HLA-DR) with the recipient have been shown to enhance graft survival, whereas HLA-DR mismatched blood transfusions will lead to immunization of the patient. The involvement of self HLA-DR suggests a role for CD4(+) regulatory T cells recognizing allopeptides in the context of self HLA class II molecules. Specific immunoregulation may be due to recognition of these allopeptides in the DR molecules of autologous T cells or dendritic cells. We tested this hypothesis on the basis of the reactivity of cell line ThoU6 which recognizes a peptide derived from an allo DR3 molecule, in the context of self DPB1*0301, and EL26, a CD4(+) T-cell clone recognizing HLA-A2 peptide in the presence of DRB1*1501. Addition of the line and clone to an assay in which the alloreactive cytotoxic T cell response (in a limiting dilution analysis) of PBLs sharing the restriction element was measured, resulted in a suppression of the anti-donor response but only when the proper peptide was added. These regulatory CD4(+) T cells were cytotoxic for targets presenting the proper peptide in the context of self MHC class II. Furthermore, these cells produced IL-10 after stimulation with the specific MHC/peptide combinations. Despite the similarity in function, EL26 and ThoU6 showed some differences in their phenotypic characteristics. Although both were CD25(+), EL26 expressed surface TGF-beta and CTLA-4, while ThoU6 did not. Similar regulatory T cells may explain the enhanced graft survival after HLA-DR shared blood transfusions either by their interaction with autologous alloreactive T cells or by modulation of autologous dendritic cells presenting the peptide involved.