TY - JOUR
T1 - A subset of virus-specific CD161+ T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML
AU - Alsuliman, Abdullah
AU - Muftuoglu, Muharrem
AU - Khoder, Ahmad
AU - Ahn, Yong Oon
AU - Basar, Rafet
AU - Verneris, Michael R.
AU - Muranski, Pawel
AU - Barrett, A. John
AU - Liu, Enli
AU - Li, Li
AU - Stringaris, Kate
AU - Armstrong-James, Darius
AU - Shaim, Hila
AU - Kondo, Kayo
AU - Imahashi, Nobuhiko
AU - Andersson, Borje
AU - Marin, David
AU - Champlin, Richard E.
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
N1 - Publisher Copyright:
© 2017, American Society of Hematology. All rights reserved.
PY - 2017/2/9
Y1 - 2017/2/9
N2 - 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-CD127hi CD28+ CD25int cells 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.
AB - 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-CD127hi CD28+ CD25int cells 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.
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U2 - 10.1182/blood-2016-05-713347
DO - 10.1182/blood-2016-05-713347
M3 - Article
C2 - 27821506
AN - SCOPUS:85014847330
SN - 0006-4971
VL - 129
SP - 740
EP - 758
JO - Blood
JF - Blood
IS - 6
ER -