A subset of virus-specific CD161+T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML.
The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4+T cells are not well-defined. Here we identify a subset of memory CD4+T cells capable of effluxing cellular toxins, including rhodamine (Rho), through the multidrug efflux protein MDR1 (also known as P-glycoprotein and ABCB1). Drug-effluxing CD4+T cells were characterized as CD161+CD95+CD45RA-CD127hiCD28+CD25intcells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4+CD161+Rho-effluxing T cells proliferated vigorously in response to stimulation with anti-CD3/CD28 beads and gave rise to CD161-progeny in vitro. These cells were also capable of self-renewal and maintained their phenotypic and functional characteristics when cultured with homeostatic cytokines. Multidrug-effluxing CD4+CD161+T cells were enriched within the viral-specific Th1 repertoire of healthy donors and patients with acute myeloid leukemia (AML) and survived exposure to daunorubicin chemotherapy in vitro. Multidrug-effluxing CD4+CD161+T cells also resisted chemotherapy-induced cytotoxicity in vivo and underwent significant expansion in AML patients rendered lymphopenic after chemotherapy, contributing to the repopulation of anti-CMV immunity. Finally, after influenza vaccination, the proportion of influenza-specific CD4+T cells coexpressing CD161 was significantly higher after 2 years compared with 4 weeks after immunization, suggesting CD161 is a marker for long-lived antigen-specific memory T cells. These findings suggest that CD4+CD161+T cells with rapid efflux capacity contribute to the maintenance of viral-specific memory T cells. These data provide novel insights into mechanisms that preserve antiviral immunity in patients undergoing chemotherapy and have implications for the development of novel immunotherapeutic approaches.
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Abdullah
A
Alsuliman
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Muharrem
M
Muftuoglu
Department of Hematology, Imperial College London, London, United Kingdom.
Ahmad
A
Khoder
Division of Hematology, Oncology, and Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Yong-Oon
YO
Ahn
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Rafet
R
Basar
Division of Hematology, Oncology, and Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Michael R
MR
Verneris
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and.
Pawel
P
Muranski
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and.
A John
AJ
Barrett
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Enli
E
Liu
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Li
L
Li
Department of Hematology, Imperial College London, London, United Kingdom.
Kate
K
Stringaris
Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Darius
D
Armstrong-James
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Hila
H
Shaim
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Kayo
K
Kondo
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Nobuhiko
N
Imahashi
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Borje
B
Andersson
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
David
D
Marin
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Richard E
RE
Champlin
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Elizabeth J
EJ
Shpall
Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX.
Katayoun
K
Rezvani
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000276:immunology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D001692:Biological Transport; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology* / Q000473:pathology / Q000821:virology; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007252:Influenza Vaccines / Q000008:administration & dosage; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology / Q000821:virology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics* / Q000276:immunology; D009975:Orthomyxoviridae / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D012235:Rhodamines / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D015704:CD4 Antigens; D007252:Influenza Vaccines; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D012235:Rhodamines; D003630:Daunorubicin