Amino Acid Transport as a Rheostat of Group 2 Innate Lymphoid Cells

Abstract

Innate lymphoid cells (ILCs) are transcriptionally poised and pre-primed cells, which are enriched at barrier sites including the lung, skin and intestinal tract. ILCs have the ability to respond rapidly to danger signals, and are integral for maintaining homeostasis and providing host immunity in response to infection. In particular, group 2 ILCs release the type 2 cytokines IL-5 and IL-13 following helminth infection. In contrast, hyperactivated ILC2 responses have been implicated in driving inflammation in allergic disease, such as asthma. Therefore, further understanding of the cell-intrinsic mechanisms which facilitate rapid type 2 innate responses in the tissue microenvironment, and the checkpoints that regulate ILC function are urgently required. It is increasingly understood that lymphocyte sensing of nutrient availability in the tissue environment is required to engage cellular metabolism and to generate the energy and biomass required to fuel immune effector function. In particular, fundamental metabolic substrates – such as essential amino acids – act to fuel biosynthesis and provide environmental cues that provide a rheostat for cellular metabolic function. In ongoing studies, we have identified that ILC2 are preferentially poised to import essential amino acids at steady state. Using conditional deletion of amino acid transporters and downstream metabolic signalling pathways in vivo we are dissecting the role of amino acid metabolism in ILC effector function at homeostasis and in the context of infection and inflammation. Our preliminary data suggest nutrient sensing and amino acids act as critical regulators of ILC2 responses. These findings may help to inform novel therapeutic strategies aimed at targeting ILC2 in health and disease.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Matthew Hepworth (Supervisor) & Mark Travis (Supervisor)