TY - JOUR
T1 - Divergent metabolic programmes control two populations of MAIT cells that protect the lung
AU - Riffelmacher, Thomas
AU - Paynich Murray, Mallory
AU - Wientjens, Chantal
AU - Chandra, Shilpi
AU - Cedillo-Castelán, Viankail
AU - Chou, Ting Fang
AU - McArdle, Sara
AU - Dillingham, Christopher
AU - Devereaux, Jordan
AU - Nilsen, Aaron
AU - Brunel, Simon
AU - Lewinsohn, David M.
AU - Hasty, Jeff
AU - Seumois, Gregory
AU - Benedict, Christopher A.
AU - Vijayanand, Pandurangan
AU - Kronenberg, Mitchell
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127−Klrg1+ and CD127+Klrg1− antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.
AB - Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127−Klrg1+ and CD127+Klrg1− antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.
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U2 - 10.1038/s41556-023-01152-6
DO - 10.1038/s41556-023-01152-6
M3 - Article
C2 - 37231163
AN - SCOPUS:85160279715
SN - 1465-7392
VL - 25
SP - 877
EP - 891
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -