TY - JOUR
T1 - T cells recognize PD(N/T)R motif common in a variable number of tandem repeat and degenerate repeat sequences of MUC1
AU - Pisarev, Vladimir M.
AU - Kinarsky, Leo
AU - Caffrey, Thomas
AU - Hanisch, Franz George
AU - Sanderson, Sam
AU - Hollingsworth, Michael A.
AU - Sherman, Simon
N1 - Funding Information:
The authors are thankful to Mss. Judi Anderson for supplying human MUC1 transgenic mice and Ms. Kristi Berger for editing the manuscript. This study was supported by grant 5RO1CA084106 from the NIH to S.S. and grant 2004-29 (LB-506) from the Nebraska Cancer and Smoking Disease Research Program, Nebraska Department of Health and Human Services to V.P.
PY - 2005/2
Y1 - 2005/2
N2 - The tumor-associated antigen MUC1 is a transmembrane glycoprotein, which is overexpressed in human carcinomas. Peptide epitopes, containing the PDTR fragment from the variable number of tandem repeat (VNTR) domains of MUC1 have been found to be immunodominant in T-cell and B-cell responses. However, little is known about the immunogenicity and specificity of T-cell epitopes from other regions of MUC1 that may also participate in immune responses against tumors. In this study, the combination of immunoinformatics, molecular modeling and a vaccine adjuvant strategy were used to predict and describe a novel T-cell epitope, SAPDNRPAL, located within the degenerate tandem repeat of MUC1. This peptide possesses structural similarity to both VNTR-derived SAPDTRPAP and Sendai virus peptide FAPGNYPAL, which are known to induce cytotoxic T lymphocytes (CTL). We found that SAPDNRPAL had a higher affinity for mouse H-Db, H-2Kb and human HLA-A2 molecules than SAPDTRPAP. A chimeric peptide (CP) containing SAPDNRPAL and an adjuvant C5a-derived decapeptide induced epitope-specific type 1 T cells in human MUC1 transgenic mice (ELISPOT). Mice that received dendritic cells (DC) pulsed with the CP or a 25-mer peptide containing the SAPDNRPAL sequence showed increased frequencies of SAPDNRPAL- and SAPDTRPAP-specific interferon-γ producing T cells. PDTR-specific antibody 214D4 reacted with both SAPDNRPAL and SAPDTRPAP (ELISA). Altogether, our data suggest that the degenerate MUC1 repeat sequence contains the immunogenic T-cell epitope SAPDNRPAL, which is cross-reactive with the VNTR-derived peptide SAPDTRPAP. We suggest that the use of immunogenic PDNR-containing epitope(s) in vaccine strategies could be beneficial for developing increased, PD(N/T)R motif-specific T-cell responses against tumors expressing MUC1.
AB - The tumor-associated antigen MUC1 is a transmembrane glycoprotein, which is overexpressed in human carcinomas. Peptide epitopes, containing the PDTR fragment from the variable number of tandem repeat (VNTR) domains of MUC1 have been found to be immunodominant in T-cell and B-cell responses. However, little is known about the immunogenicity and specificity of T-cell epitopes from other regions of MUC1 that may also participate in immune responses against tumors. In this study, the combination of immunoinformatics, molecular modeling and a vaccine adjuvant strategy were used to predict and describe a novel T-cell epitope, SAPDNRPAL, located within the degenerate tandem repeat of MUC1. This peptide possesses structural similarity to both VNTR-derived SAPDTRPAP and Sendai virus peptide FAPGNYPAL, which are known to induce cytotoxic T lymphocytes (CTL). We found that SAPDNRPAL had a higher affinity for mouse H-Db, H-2Kb and human HLA-A2 molecules than SAPDTRPAP. A chimeric peptide (CP) containing SAPDNRPAL and an adjuvant C5a-derived decapeptide induced epitope-specific type 1 T cells in human MUC1 transgenic mice (ELISPOT). Mice that received dendritic cells (DC) pulsed with the CP or a 25-mer peptide containing the SAPDNRPAL sequence showed increased frequencies of SAPDNRPAL- and SAPDTRPAP-specific interferon-γ producing T cells. PDTR-specific antibody 214D4 reacted with both SAPDNRPAL and SAPDTRPAP (ELISA). Altogether, our data suggest that the degenerate MUC1 repeat sequence contains the immunogenic T-cell epitope SAPDNRPAL, which is cross-reactive with the VNTR-derived peptide SAPDTRPAP. We suggest that the use of immunogenic PDNR-containing epitope(s) in vaccine strategies could be beneficial for developing increased, PD(N/T)R motif-specific T-cell responses against tumors expressing MUC1.
KW - C5a-derived peptide
KW - Class I MHC binding
KW - Cross-reactive T-cell epitopes
KW - Degenerate tandem repeat MUC1
KW - ELISPOT
KW - Mucin
UR - http://www.scopus.com/inward/record.url?scp=12344255938&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=12344255938&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2004.10.004
DO - 10.1016/j.intimp.2004.10.004
M3 - Article
C2 - 15652762
AN - SCOPUS:12344255938
SN - 1567-5769
VL - 5
SP - 315
EP - 330
JO - International Immunopharmacology
JF - International Immunopharmacology
IS - 2
ER -