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

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Blood, ISSN: 1528-0020, Vol: 129, Issue: 6, Page: 740-758

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Alsuliman, Abdullah; Muftuoglu, Muharrem; Khoder, Ahmad; Ahn, Yong-Oon; Basar, Rafet; Verneris, Michael R; Muranski, Pawel; Barrett, A John; Liu, Enli; Li, Li; Stringaris, Kate; Armstrong-James, Darius; Shaim, Hila; Kondo, Kayo; Imahashi, Nobuhiko; Andersson, Borje; Marin, David; Champlin, Richard E; Shpall, Elizabeth J; Rezvani, Katayoun Show More Hide
American Society of Hematology
Biochemistry, Genetics and Molecular Biology; Immunology and Microbiology; Medicine
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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 CD161CD95CD45RACD127CD28CD25 cells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4CD161Rho-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 CD4CD161 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 CD4CD161 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 CD4CD161 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.