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Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses
Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses

Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens-including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 are found to be uniquely preprimed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine-producing capacity of ILC2. Mechanistically, amino acid uptake determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.

Amino Acids/metabolism, Cytokines/metabolism, Immunity, Innate, Lymphocytes/metabolism, Mucous Membrane/metabolism
0022-1007
Hodge, Suzanne H
74e320b3-4db7-45c5-a5e5-1bec724e31e8
Krauss, Maria Z
7b21de00-eede-45ac-877b-f36030004b91
Kaymak, Irem
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King, James I
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Howden, Andrew J M
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Panic, Gordana
b5c18deb-f7c2-4922-b266-bedcf63860d0
Grencis, Richard K
d510326b-f979-450d-b063-cefe20393ee2
Swann, Jonathan R
7c11a66b-f4b8-4dbf-aa17-ad8b0561b85c
Sinclair, Linda V
753914b4-4902-4d6b-9bd3-db94e0ee971a
Hepworth, Matthew R
d4cc1c88-7356-4d99-8031-f4033916f1a7
Hodge, Suzanne H
74e320b3-4db7-45c5-a5e5-1bec724e31e8
Krauss, Maria Z
7b21de00-eede-45ac-877b-f36030004b91
Kaymak, Irem
6953d6e3-5e19-4e4e-9d33-0cfede0424c8
King, James I
c954c6d5-f777-4a70-b5a8-b8cc598c4e75
Howden, Andrew J M
8c07e35e-3865-4192-a6cd-764d353e2937
Panic, Gordana
b5c18deb-f7c2-4922-b266-bedcf63860d0
Grencis, Richard K
d510326b-f979-450d-b063-cefe20393ee2
Swann, Jonathan R
7c11a66b-f4b8-4dbf-aa17-ad8b0561b85c
Sinclair, Linda V
753914b4-4902-4d6b-9bd3-db94e0ee971a
Hepworth, Matthew R
d4cc1c88-7356-4d99-8031-f4033916f1a7

Hodge, Suzanne H, Krauss, Maria Z, Kaymak, Irem, King, James I, Howden, Andrew J M, Panic, Gordana, Grencis, Richard K, Swann, Jonathan R, Sinclair, Linda V and Hepworth, Matthew R (2023) Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses. The Journal of Experimental Medicine, 220 (3), [e20221073]. (doi:10.1084/jem.20221073).

Record type: Article

Abstract

Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens-including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 are found to be uniquely preprimed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine-producing capacity of ILC2. Mechanistically, amino acid uptake determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.

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Accepted/In Press date: 16 December 2022
Published date: 6 March 2023
Additional Information: © 2022 Hodge et al.
Keywords: Amino Acids/metabolism, Cytokines/metabolism, Immunity, Innate, Lymphocytes/metabolism, Mucous Membrane/metabolism

Identifiers

Local EPrints ID: 477046
URI: http://eprints.soton.ac.uk/id/eprint/477046
ISSN: 0022-1007
PURE UUID: 56a378ae-31b5-4893-8d23-c87c099721fb
ORCID for Jonathan R Swann: ORCID iD orcid.org/0000-0002-6485-4529

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Date deposited: 24 May 2023 16:54
Last modified: 17 Aug 2024 02:04

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Contributors

Author: Suzanne H Hodge
Author: Maria Z Krauss
Author: Irem Kaymak
Author: James I King
Author: Andrew J M Howden
Author: Gordana Panic
Author: Richard K Grencis
Author: Linda V Sinclair
Author: Matthew R Hepworth

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