Identification of naturally processed CD4 T cell epitopes from the prostate-specific antigen kallikrein 4 using peptide-based in vitro stimulation.
Kallikrein (KLK)4 is a recently described member of the tissue kallikrein gene family that is specifically expressed in normal and prostate tumor tissues. The tissue-specific expression profile of this molecule suggests that it might be useful as a vaccine candidate against prostate cancer. To examine the presence of CD4 T cells specific for KLK4 in PBMC of normal individuals, a peptide-based in vitro stimulation protocol was developed that uses overlapping KLK4-derived peptides spanning the majority of the KLK4 protein. Using this methodology, three naturally processed CD4 epitopes derived from the KLK4 sequence are identified. These epitopes are restricted by HLA-DRB1*0404, HLA-DRB1*0701, and HLA-DPB1*0401 class II alleles. CD4 T cell clones specific for these epitopes are shown to efficiently and specifically recognize both recombinant KLK4 protein and lysates from prostate tumor cell lines virally infected to express KLK4. CD4 T cells specific for these KLK4 epitopes are shown to exist in PBMC from multiple male donors that express the relevant class II alleles, indicating that a CD4 T cell repertoire specific for KLK4 is present and potentially expandable in prostate cancer patients. The demonstration that KLK4-specific CD4 T cells exist in the peripheral circulation of normal male donors and the identification of naturally processed KLK4-derived CD4 T cell epitopes support the use of KLK4 in whole gene-, protein-, or peptide-based vaccine strategies against prostate cancer. Furthermore, the identification of naturally processed KLK4-derived epitopes provides valuable tools for monitoring preexisting and vaccine-induced responses to this molecule.
Hural
John A
JA
Corixa Corporation and Infectious Disease Research Institute, Seattle, WA 98104, USA.
Friedman
Rachel S
RS
McNabb
Andria
A
Steen
Sean S
SS
Henderson
Robert A
RA
Kalos
Michael
M
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D002458:Cell Fractionation; D002461:Cell Line, Transformed; D002999:Clone Cells; D017124:Conserved Sequence / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006681:HLA-D Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D007113:Immunity, Innate / Q000235:genetics; D007610:Kallikreins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018984:Epitopes, T-Lymphocyte; D006681:HLA-D Antigens; D010446:Peptide Fragments; D011994:Recombinant Proteins; D007610:Kallikreins; C120801:kallikrein 4; D017430:Prostate-Specific Antigen