An old dog with ‘new’ tricks: the MDR1 transporter in T cell-mediated immunity

Abstract

Abstract Multidrug Resistance Protein 1 (MDR1) is an orphan ATP-binding cassette transporter, originally discovered for removing cytostatic drugs from resistant tumor cells. However, MDR1 is also functionally expressed in many normal cell types. Work from our group has shown that MDR1 is constitutively expressed in cytotoxic T cells (CTLs), where it promotes CTL-mediated immunity to infection. Adoptive transfer of Lymphocytic choriomeningitis virus (LCMV)-specific MDR1 (Abcb1a/b)-deficient naïve CTLs into wild-type recipients, followed by LCMV infection, has revealed that MDR1-deficient CTLs fail to accumulate to wild-type levels in response to either acute (Armstrong) or chronic (Clone-13) LCMV infection. This defective accumulation is observed as early as 5-days post-infection, suggesting that endogenous MDR1 transport activity may preferentially regulate early T cell receptor (TCR)-elicited CTL functions. New single cell (sc)RNA-seq experiments, coupled with RNA velocity and lineage trajectory analyses, suggest that MDR1 expression is induced rapidly during TCR activation, coinciding with the induction of other genes involved in mitochondrial and redox metabolism. In vitro-activated CTLs lacking MDR1 also experience oxidative stress, mitochondrial dysfunction and display mitochondrial localization of MDR1. Together, these data support a new model of MDR1 function, in which MDR1-dependent transport of endogenous substrates suppresses oxidative stress and supports redox homeostasis during periods of metabolic activation. In turn, these concepts provide a novel framework for improving the efficacy and durability of vaccines, and for elucidating metabolic vulnerabilities of multidrug-resistant cancers.