A subset of virus-specific CD161+ T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML

Abdullah Alsuliman, Muharrem Muftuoglu, Ahmad Khoder, Yong Oon Ahn, Rafet Basar, Michael R. Verneris, Pawel Muranski, A. John Barrett, Enli Liu, Li Li, Kate Stringaris, Darius Armstrong-James, Hila Shaim, Kayo Kondo, Nobuhiko Imahashi, Borje Andersson, David Marin, Richard E. Champlin, Elizabeth J. Shpall, Katayoun Rezvani

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)740-758
Number of pages19
JournalBlood
Volume129
Issue number6
DOIs
StatePublished - Feb 9 2017

Bibliographical note

Funding Information:
This work was funded in part by National Institutes of Health, National Cancer Institute grants P01 CA148600-02 and RO1 CA061508-18. The flow studies were performed in the Flow Cytometry and Cellular Imaging Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672.

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