A PD-1-ST2 axis controls Th2 effector function in tissue via a metabolic checkpoint

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Type 2 immune responses characterise both helminth infections and atopic disease such as allergy or asthma, but a better understanding of the mechanisms that regulate these responses is key to improving therapeutic and vaccination strategies. Immuno-metabolic studies over the last two decades have suggested T cell activation broadly requires rapid increases in glycolysis and oxidative phosphorylation. In contrast, we show that CD4 + T helper 2 (Th2) cells activated in vivo , using models of helminth infection, do not acquire a glycolytic metabolism. Instead, we show that Th2 cells solely increase their oxidative metabolism, associated with increased fatty acid uptake. Rather than contributing directly to effector function, our data reveal that Th2 cells switch to fatty acid oxidation downstream of PD-1 signalling to promote expression of the IL-33 receptor (ST2). These data provide insight into the spatial regulation of T cell metabolism, and suggest that PD-1 blockade therapies may be effective in Th2 disorders.

Authors 5

1. Graham A. Heieis corresponding Aachen Department of Parasitology, Leiden University Medical Center

   University of British Columbia · Leiden University Medical Center · University of Glasgow

   Affiliation as printed

   Centre for Immunobiology, School of Infection & Immunity, University of Glasgow, Glasgow, United Kingdom

   Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

   Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands

2. Bart Everts Aachen Department of Parasitology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands

3. Craig W. Roberts

   University of Strathclyde

   Affiliation as printed

   Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom

4. Rick M. Maizels

   University of Glasgow

   Affiliation as printed

   Wellcome Trust Centre for Integrative Parasitology, School of Infection & Immunity, University of Glasgow, Glasgow, United Kingdom

5. Georgia Perona‐Wright

   University of British Columbia · University of Glasgow

   Affiliation as printed

   Centre for Immunobiology, School of Infection & Immunity, University of Glasgow, Glasgow, United Kingdom

   Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

   Wellcome Trust Centre for Integrative Parasitology, School of Infection & Immunity, University of Glasgow, Glasgow, United Kingdom