Metabolic fuel choices control MAIT cell functions at homeostasis and after infection

Abstract

Mucosal-associated-invariant-T (MAIT) cells are an innate-like T cell subset that recognizes microbial-derived vitamin B metabolites. In contrast to conventional T cells, MAIT cells have an antigen-experienced phenotype and express memory markers by default. When activated, MAIT cells rapidly produce copious amounts of cytokines, resembling IFNg+ Th1- or IL-17+ Th17 effectors cells. While memory-like vs effector-like states in conventional CD4 and CD8 T cells are controlled by mutually exclusive metabolic states, the question remains as to which metabolic programs MAIT cells adopt at steady-state and after infection. Here we integrate scRNA-seq analysis with single-cell metabolic characterization of MAIT cells from humans and mice. We discovered a memory-like metabolic program that is acquired in the thymus and at steady state in the periphery. We identify a novel cluster of circulatory MAIT cells which is metabolically similar to IFNg+ MAIT1-like cells and preferentially consumes glucose. MAIT17 clusters, most prevalent in mice, uniquely engage in fatty acid uptake and mitochondrial metabolism. Following exposure to bacteria, mouse MAIT cells expand as CD127−KLRG1+ and CD127+KLRG1− populations that adopt divergent transcriptomic and metabolic profiles with enhanced functionality. They remain altered long-term. CD127+, but not KLRG1+ MAIT cells engage in MAIT17-like metabolic and effector pathways and protect mice from lung infection with Streptococcus pneumoniae. In contrast, KLRG1+ MAIT cells depend on Hif1a-driven glycolysis and remain metabolically dormant but ready to respond, more rapidly engaging multiple metabolic programs to protect from viral infection. Supported by R01AI137230 (MK), R01AI71922 (MK), Wellcome Trust 210842_Z_18_Z (TR)

Transcriptomes and metabolism define mouse and human MAIT cell populations

“…Furthermore, supplementation with the trichloroacetic acid metabolite α-ketoglutarate augmented human MAIT cell effector capacity ( 66 ), providing a further connection between metabolism and MAIT cell function. These data and other studies ( 57 ) suggest a causal link between metabolism and MAIT cell function.…”

“…S9B). KLRG1 + lung MAIT cells were virtually undetectable at steady state in C57BL/6 mice, but this was found to be a marker for memory-like MAIT1 cells in vaccinated mice ( 57 ). These data suggested that removal from SPF conditions decreased MAIT17 cells with perhaps an increase in MAIT1 cells.…”

“…Recently, we reported that weeks after bacterial infection, populations of mouse lung memory-like MAIT1 and MAIT17 cells have metabolic features that are different from one another and from steady-state lung MAIT17 cells. Furthermore, these antigen-adapted MAIT1 and MAIT17 cells greatly alter their metabolism after reactivation ( 57 ). Therefore, MAIT cell metabolic features are altered both short term and long term after antigenic stimulation.…”

Iron is critical for mucosal-associated invariant T cell metabolism and effector functions

“…Immune responses are metabolically intense processes, with significant energy demands required to support de novo generation of biosynthetic intermediates 27 . The metabolic processes and nutrient requirements that govern MAIT cell effector responses are rapidly emerging but still incomplete 10,11,12,13,28 . Iron is an essential microelement and is critical for almost all living organisms, including humans and the majority of microbes 15 .…”

“…Recently, several studies have highlighted the importance of metabolism for MAIT cell functional responses 9 . Our group and others have demonstrated that MAIT cells are reliant on glycolysis to support their production of IFNg and Granzyme B 10,11,12 , whereas IL-17 production by MAIT cells has been linked to mitochondrial metabolism 13,14 . However, our knowledge of the nutritional requirements of MAIT cells remains limited.…”