Peripheral blood-derived virus-specific memory stem T cells mature to functional effector memory subsets with self-renewal potency.
Memory T cells expressing stem cell-like properties have been described recently. The capacity of self-renewal and differentiation into various memory/effector subsets make them attractive for adoptive T cell therapy to combat severe virus infections and tumors. The very few reports on human memory stem T cells (T(SCM)) are restricted to analyses on polyclonal T cells, but extensive data on Ag-specific T(SCM )are missing. This might be due to their very low frequency limiting their enrichment and characterization. In this article, we provide functional and phenotypic data on human viral-specific T(SCM), defined as CD8(+)CD45RA(+)CCR7(+)CD127(+)CD95(+). Whereas <1% of total T cells express the T(SCM) phenotype, human CMV-specific T(SCM) can be detected at frequencies similar to those seen in other subsets, resulting in ∼ 1 /10,000 human CMV-specific T(SCM). A new virus-specific expansion protocol of sort-purified T(SCM) reveals both upregulation of various T cell subset markers and preservation of their stem cell phenotype in a significant proportion, indicating both self-renewal and differentiation potency of virus-specific T cells sharing their TCR repertoire. Furthermore, we describe a simplified culture protocol that allows fast expansion of virus-specific T(SCM) starting from a mixed naive T/T(SCM) pool of PBLs. Due to the clinical-grade compatibility, this might be the basis for novel cell therapeutic options in life-threatening courses of viral and tumor disease.
Institute for Medical Immunology, Charité University Medicine Berlin, D-13353 Berlin, Germany; Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, D-13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany; michael.schmueck-henneresse@charite.de.
Michael
M
Schmueck-Henneresse
Institute for Medical Immunology, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Radwa
R
Sharaf
Institute for Medical Immunology, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Katrin
K
Vogt
Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Benjamin J D
BJ
Weist
Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany; Department for Pediatric Pulmonology and Immunology, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Sybille
S
Landwehr-Kenzel
Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, D-13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Henrike
H
Fuehrer
Institute for Medical Immunology, Charité University Medicine Berlin, D-13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Anke
A
Jurisch
Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany; Marien Hospital Herne, Ruhr University Bochum, D-44625 Herne, Germany; and.
Nina
N
Babel
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030.
Cliona M
CM
Rooney
Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, D-13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Petra
P
Reinke
Institute for Medical Immunology, Charité University Medicine Berlin, D-13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, D-13353 Berlin, Germany;
Hans-Dieter
HD
Volk
D019264:Adoptive Transfer; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D018655:Lymphocyte Count; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D054400:Receptors, CCR7 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013234:Stem Cells / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
C515370:CCR7 protein, human; D016827:CD8 Antigens; C491901:FAS protein, human; D053699:Interleukin-7 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; D019014:fas Receptor; D017493:Leukocyte Common Antigens