Using fluorescent HLA-A*0201 tetramers containing the immunodominant Melan-A/MART-1 (Melan-A) tumor-associated antigen (Ag), we previously observed that metastatic lymph nodes of melanoma patients contain high numbers of Ag-experienced Melan-A–specific cytolytic T lymphocytes (CTLs). In this paper, we enumerated and characterized ex vivo Melan-A–specific cells in peripheral blood samples from both melanoma patients and healthy individuals. High frequencies (≥1 in 2,500 CD8+ T cells) of Melan-A–specific cells were found in 10 out of 13 patients, and, surprisingly, in 6 out of 10 healthy individuals. Virtually all Melan-A–specific cells from 6 out of 6 healthy individuals and from 7 out of 10 patients displayed a naive CD45RAhi/RO− phenotype, whereas variable proportions of Ag-experienced CD45RAlo/RO+ Melan-A–specific cells were observed in the remaining 3 patients. In contrast, ex vivo influenza matrix–specific CTLs from all individuals exhibited a CD45RAlo/RO+ memory phenotype as expected. Ag specificity of tetramer-sorted A2/Melan-A+ cells from healthy individuals was confirmed after mitogen-driven expansion. Likewise, functional limiting dilution analysis and interferon γ ELISPOT assays independently confirmed that most of the Melan-A–specific cells were not Ag experienced. Thus, it appears that high frequencies of naive Melan-A–specific CD8+ T cells can be found in a large proportion of HLA-A*0201+ individuals. Furthermore, as demonstrated for one patient followed over time, dramatic phenotype changes of circulating Melan-A–specific cells can occur in vivo.
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6 September 1999
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September 06 1999
High Frequencies of Naive Melan-a/Mart-1–Specific Cd8+ T Cells in a Large Proportion of Human Histocompatibility Leukocyte Antigen (Hla)-A2 Individuals
Mikaël J. Pittet,
Mikaël J. Pittet
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
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Danila Valmori,
Danila Valmori
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
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P. Rod Dunbar,
P. Rod Dunbar
cInstitute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
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Daniel E. Speiser,
Daniel E. Speiser
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
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Danielle Liénard,
Danielle Liénard
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
bMultidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
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Ferdy Lejeune,
Ferdy Lejeune
bMultidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
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Katharina Fleischhauer,
Katharina Fleischhauer
dTissue Typing Laboratory, Department of Biology and Biotechnology (DIBIT), Istituto Scientifico H.S. Raffaele, 20132 Milano, Italy
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Vincenzo Cerundolo,
Vincenzo Cerundolo
cInstitute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
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Jean-Charles Cerottini,
Jean-Charles Cerottini
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
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Pedro Romero
Pedro Romero
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
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Mikaël J. Pittet
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
Danila Valmori
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
P. Rod Dunbar
cInstitute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Daniel E. Speiser
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
Danielle Liénard
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
bMultidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
Ferdy Lejeune
bMultidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
Katharina Fleischhauer
dTissue Typing Laboratory, Department of Biology and Biotechnology (DIBIT), Istituto Scientifico H.S. Raffaele, 20132 Milano, Italy
Vincenzo Cerundolo
cInstitute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Jean-Charles Cerottini
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
Pedro Romero
aFrom the Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
1used in this paper: CTL, cytolytic T lymphocyte; CTLp, cytolytic T lymphocytes precursor(s); LDA, limiting dilution analysis; Melan-A, Melan-A/MART-1
Received:
April 01 1999
Revision Requested:
June 30 1999
Accepted:
July 06 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 1999 The Rockefeller University Press
1999
The Rockefeller University Press
J Exp Med (1999) 190 (5): 705–716.
Article history
Received:
April 01 1999
Revision Requested:
June 30 1999
Accepted:
July 06 1999
Citation
Mikaël J. Pittet, Danila Valmori, P. Rod Dunbar, Daniel E. Speiser, Danielle Liénard, Ferdy Lejeune, Katharina Fleischhauer, Vincenzo Cerundolo, Jean-Charles Cerottini, Pedro Romero; High Frequencies of Naive Melan-a/Mart-1–Specific Cd8+ T Cells in a Large Proportion of Human Histocompatibility Leukocyte Antigen (Hla)-A2 Individuals. J Exp Med 6 September 1999; 190 (5): 705–716. doi: https://doi.org/10.1084/jem.190.5.705
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