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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 and Katayoun Rezvani

Key Points

  • Human CD4+CD161+ T cells display unique properties including MDR1-mediated drug efflux capacity and quiescence.

  • CD4+CD161+ T cells are enriched within the long-lived viral-specific Th1 memory repertoire in humans.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

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+CD45RACD127hiCD28+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.

  • Submitted May 2, 2016.
  • Accepted October 3, 2016.
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