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Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes.

Theobald M, Biggs J, Hernández J, Lustgarten J, Labadie C, Sherman LA - J. Exp. Med. (1997)

Bottom Line: Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer.A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells.The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53-/-) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1-restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53-/- transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53-/- and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53-/- mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

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The Mu WT p53.261-269 peptide is endogenously processed and presented in association with HLA-A2.1 on the surface of vvA2.1–infected murine cells. The A2.1 restricted, Mu WT p53.261-269  peptide specific CTL were used as effectors in a 5 h 51Cr-release assay in  which 10(3) tumor cells (A), or 10(3) Mu p53 transfectants (B) were infected with a vaccinia recombinant expressing either the HLA-A2.1 molecule (closed triangles), or gp 160 (closed circles).
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Figure 3: The Mu WT p53.261-269 peptide is endogenously processed and presented in association with HLA-A2.1 on the surface of vvA2.1–infected murine cells. The A2.1 restricted, Mu WT p53.261-269 peptide specific CTL were used as effectors in a 5 h 51Cr-release assay in which 10(3) tumor cells (A), or 10(3) Mu p53 transfectants (B) were infected with a vaccinia recombinant expressing either the HLA-A2.1 molecule (closed triangles), or gp 160 (closed circles).

Mentions: Previous studies had demonstrated the Hu analogue of the Mu p53.261-269 peptide was endogenously processed and presented in association with A2.1 (23). However, as the Mu and Hu peptides differed at one residue (Table 1) it was possible this difference affected the presentation of the Mu peptide, resulting in incomplete tolerance induction. This could explain its recognition in both p53-deficient and -sufficient animals. To determine if the Mu WT p53.261-269 peptide was presented by A2.1 on Mu cells, a transfectant of the mouse 10(3) cell line which expresses high levels of Mu p53, was infected with a recombinant strain of vaccinia virus that expresses the A2.1 molecule, vv-A2.1. As a control for the effect of viral infection, cells were infected by a recombinant strain encoding the gp160 of HIV-1 (vPE16). As presented in Fig. 3, the 10(3) Mu p53 transfectant expressing the A2.1 molecule was specifically lysed by a CTL population specific for the Mu 261-269 peptide epitope. Neither the p53-deficient parental line, 10(3), nor the 10(3) Mu p53 transfectant infected with vPE16 rather than vv-A2.1 were lysed by these same effectors. Therefore, the Mu WT p53.261269 peptide is presented by cells that express both Mu p53 and A2.1.


Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes.

Theobald M, Biggs J, Hernández J, Lustgarten J, Labadie C, Sherman LA - J. Exp. Med. (1997)

The Mu WT p53.261-269 peptide is endogenously processed and presented in association with HLA-A2.1 on the surface of vvA2.1–infected murine cells. The A2.1 restricted, Mu WT p53.261-269  peptide specific CTL were used as effectors in a 5 h 51Cr-release assay in  which 10(3) tumor cells (A), or 10(3) Mu p53 transfectants (B) were infected with a vaccinia recombinant expressing either the HLA-A2.1 molecule (closed triangles), or gp 160 (closed circles).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196170&req=5

Figure 3: The Mu WT p53.261-269 peptide is endogenously processed and presented in association with HLA-A2.1 on the surface of vvA2.1–infected murine cells. The A2.1 restricted, Mu WT p53.261-269 peptide specific CTL were used as effectors in a 5 h 51Cr-release assay in which 10(3) tumor cells (A), or 10(3) Mu p53 transfectants (B) were infected with a vaccinia recombinant expressing either the HLA-A2.1 molecule (closed triangles), or gp 160 (closed circles).
Mentions: Previous studies had demonstrated the Hu analogue of the Mu p53.261-269 peptide was endogenously processed and presented in association with A2.1 (23). However, as the Mu and Hu peptides differed at one residue (Table 1) it was possible this difference affected the presentation of the Mu peptide, resulting in incomplete tolerance induction. This could explain its recognition in both p53-deficient and -sufficient animals. To determine if the Mu WT p53.261-269 peptide was presented by A2.1 on Mu cells, a transfectant of the mouse 10(3) cell line which expresses high levels of Mu p53, was infected with a recombinant strain of vaccinia virus that expresses the A2.1 molecule, vv-A2.1. As a control for the effect of viral infection, cells were infected by a recombinant strain encoding the gp160 of HIV-1 (vPE16). As presented in Fig. 3, the 10(3) Mu p53 transfectant expressing the A2.1 molecule was specifically lysed by a CTL population specific for the Mu 261-269 peptide epitope. Neither the p53-deficient parental line, 10(3), nor the 10(3) Mu p53 transfectant infected with vPE16 rather than vv-A2.1 were lysed by these same effectors. Therefore, the Mu WT p53.261269 peptide is presented by cells that express both Mu p53 and A2.1.

Bottom Line: Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer.A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells.The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53-/-) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1-restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53-/- transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53-/- and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53-/- mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

Show MeSH
Related in: MedlinePlus