By stimulating peripheral blood mononuclear cells of four healthy donors with a mixture of overlapping peptides representing the core domain of p53, we established two CD4+ alphabeta T cell clones and four lines that recognized wild-type and mutant p53 proteins as well as p53 self peptides in an HLA class II-restricted fashion. Two T cell lines established from two unrelated donors reacted to the p53 peptide (p)153-166 and p108-122, respectively, in the context of DP5 molecules. Two T cell clones established from two other unrelated donors were specific for p193-204 in the context of DRB1*1401 and for p153-165 in the context of DP5, respectively. These two T cell clones responded almost equally to both wild-type and four mutant recombinant p53 proteins. The proliferative responses of these T cell clones to p53 recombinant proteins were augmented by heat denaturing, thereby suggesting that altered conformation of the protein facilitates proteolytic processing to produce antigenic peptides. The DRB1*1401-restricted T cell clone specific for p193-204 killed a B lymphoblastoid cell line homozygous for HLA-DRB1*1401 when the cell line was pre-pulsed with p53 protein as well as peptide. These results indicate that CD4+ T cells reactive to p53 do exist in healthy individuals and the epitopes are probably ignored by the immune system under physiological conditions. It is suggested that such epitopes stimulate T cells to induce anti-p53 antibody production in cancer patients as previously reported by others. The possible involvement of p53-reactive T cells in anti-tumor immunity is discussed.

HumanCD4+T-cells recognize antigenic peptides in the context of humanleukocyte antigen (HLA) class II molecules and produce various lymphokines to proliferate and activate other cells. It was once considered that the T-cell response is an all or nothing type event, but recent studies have clearly indicated that T-cells show manydifferent types of activation in recognition of altered ligands for T-cell receptors (TCR). In this review, wesummarizeour recent findings on the human CD4+T-cell response to altered peptide ligands (APL); peptides carrying single residue substitutions in antigenic peptides. Weobserved the following: 1) TCRantagonism for T-cell clones reactive to non-self or autoantigenic peptides, 2) partial activation (agonism) without cell proliferation, including production of lymphokinesand increases in cell size, and in expression levels of several cell surface proteins or survival time in the absence of antigenic stimulus, 3) augmentation in cell proliferation and production of interferon-y (IFN-y) and granulocyte monocyte colony stimulating factor (GM-CSF), 4) augmentation of interleukin (IL)-12 production by antigen presenting cell (APC) and the subsequent augmented production of IFN-y by T-cells. This information provides basic knowledge regarding the characteristics of T-cell recognition of antigens and the subsequent activation, and a novel method for modification of humanT-cell responses by altered peptide ligands (APLs), as a possible candidate for antigen-specific immunopotentiating or immunosuppressive therapy against autoimmune diseases, allergies, infectious diseases and malignant tumors. (Internal Medicine 37: 804-817, 1998)

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