Tissue-specific metabolic profile drives iNKT cell function during obesity and liver injury
Cristhiane Fávero de Aguiar, Felipe Corrêa‐da‐Silva, Michelangelo Bauwelz Gonzatti, Monara Kaélle Sérvulo Cruz Angelim, Marco Antônio M. Pretti, Gustavo Gastão Davanzo, Bianca Gazieri Castelucci, Lauar de Brito Monteiro, Gisele Castro, João Victor Virgílio-da-Silva, Guilherme Ribeiro, Vitor Jaccomo, Mirella Cristiny Pereira de Andrade, Webster Leonardo Guimarães da Costa, Victor Gambarini, Fernanda Fernandes Terra, José C. Alves‐Filho, Niels Olsen Saraiva Câmara, Mariana Boroni, Alexandre C. Keller, Pedro M. Moraes‐Vieira
Abstract
Invariant natural killer T (iNKT) cells are a distinct population of lymphocytes characterized by their reactivity to glycolipids presented by CD1d. iNKT cells are found throughout the body, and little is known about their tissue-specific metabolic regulation. Here, we show that splenic and hepatic iNKT cells are metabolically comparable and rely on glycolytic metabolism to support their activation. Deletion of the pyruvate kinase M2 (Pkm2) gene in splenic and hepatic iNKT cells impairs their response to specific stimulation and their ability to mitigate acute liver injury. In contrast, adipose tissue (AT) iNKT cells exhibit a distinctive immunometabolic profile, with AMP-activated protein kinase (AMPK) being necessary for their function. AMPK deficiency impairs AT-iNKT physiology, blocking their capacity to maintain AT homeostasis and their ability to regulate AT inflammation during obesity. Our work deepens our understanding on the tissue-specific immunometabolic regulation of iNKT cells, which directly impacts the course of liver injury and obesity-induced inflammation.