Human MAIT cells show metabolic quiescence with rapid glucose‐dependent upregulation of granzyme B upon stimulation

Abstract

Mucosal‐associated invariant T (MAIT) cells are a well‐characterized innate‐like T cell population abundant in the human liver, peripheral tissues and blood. MAIT cells serve in the first line of defense against infections, through engagement of their T cell receptor, which recognizes microbial metabolites presented on MR1, and through cytokine‐mediated triggering. Typically, they show a quiescent memory phenotype but can undergo rapid upregulation of effector functions including cytolysis upon stimulation. T cells profoundly change their cellular metabolism during their maturation and activation. We sought to determine how MAIT cell metabolism may facilitate both the long‐term memory phase in tissue and the transition to rapid effector function. Here, we show, by flow cytometric metabolism assays and extracellular flux analysis that, despite an effector‐memory profile, human MAIT cells are metabolically quiescent in a resting state comparable to naïve and central memory T cells. Upon stimulation, they rapidly increase uptake of glucose and show a concomitant upregulation of the effector molecules notably granzyme B, which is impaired by inhibition of glycolysis with 2‐deoxyglucose. These findings suggest that MAIT cells share some metabolic characteristics of both resting and effector T cell subsets, with a rapid transition upon triggering. Metabolic programming of this cell type may be of interest in understanding and modulating their function in infectious diseases and cancer.

Mucosal-Associated Invariant T cell in liver diseases

“…Once activated, MAIT cells show their effector functions, including producing cytokines and inducing cytolysis. Sometimes these processes were accompanied with the increasing uptake of glucose [44]. Furthermore, it was also reported that the mTORC1 signaling was relevant to the glycolysis of MAIT cells, leading to altered MAIT cell responses [45].…”

Immunology & Cell Biology's top 10 original research articles 2017–2018

“…Zinser et al . Human MAIT cells show metabolic quiescence with rapid glucose‐dependent upregulation of granzyme B upon stimulation Cameron & Godfrey.…”

“…Another key topic covered in our top 10 publications is the identification and characterization of innate and innate‐like lymphocytes including innate lymphoid cells (ILC), mucosal‐associated invariant T (MAIT) cells, and natural killer T (NKT) cells . The study by Steigler et al .…”

“…and Cameron et al . dissect and characterize the metabolic program of MAIT cells and the functional diversity of NKT cell subsets, respectively, and exquisitely highlight the unique functional attributes of these innate‐like T cells.…”

“…3 Using CCR2 À/À animals, which only manifested a reduced inflammatory monocyte recruitment in the lungs after respiratory vaccinia virus infection, Desai et al investigated not only the short-term impact but also the longterm consequence of the absence of inflammatory monocytes and reported a significant impairment in the long-term maintenance but not generation of the CXCR3 hi CX3CR1 lo CD8 T RM -cell subset. 3 Another key topic covered in our top 10 publications is the identification and characterization of innate and innatelike lymphocytes including innate lymphoid cells (ILC), 4 mucosal-associated invariant T (MAIT) cells, 6 and natural killer T (NKT) cells. 7 The study by Steigler et al reveals a role for lung ILC in inducing c-interferon (IFN-c) production after mucosal BCG vaccination and highlights a new pathway to target to enhance antimycobacterial protection.…”