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

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