Polarized mitochondria as guardians of NK cell fitness

Laura Surace (1) , Jean-Marc Doisne (1) , Pedro Escoll (2) , Solenne Marie (1) , Valerie Dardalhon (3) , Carys Croft (1, 4) , Anna Thaller (1, 4) , Davide Topazio (5) , Angelo Sparaneo (6) , Antonia Cama (7) , Olimpia Musumeci (8) , Aurelio d'Ecclesia (5) , Carmen Buchrieser (2) , Naomi Taylor (3) , James Di Santo (1)

1 Immunité Innée - Innate Immunity
2 Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria
3 IGMM - Institut de Génétique Moléculaire de Montpellier
4 ED562 - BioSPC - École Doctorale Bio Sorbonne Paris Cité [Paris]
5 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
6 Fondazione IRCCS Casa Sollievo della Sofferenza - Laboratorio di Oncologia [San Giovanni Rotondo, Italy]
7 University of Naples Federico II = Università degli studi di Napoli Federico II
8 Department of Clinical and Experimental Medicine [Messina, Italy]

Distinct metabolic demands accompany lymphocyte differentiation into short-lived effector and long-lived memory cells. How bioenergetics processes are structured in innate natural killer (NK) cells remains unclear. We demonstrate that circulating human CD56Dim (NKDim) cells have fused mitochondria and enhanced metabolism compared with CD56Br (NKBr) cells. Upon activation, these 2 subsets showed a dichotomous response, with further mitochondrial potentiation in NKBr cells vs paradoxical mitochondrial fission and depolarization in NKDim cells. The latter effect impaired interferon-γ production, but rescue was possible by inhibiting mitochondrial fragmentation, implicating mitochondrial polarization as a central regulator of NK cell function. NKDim cells are heterogeneous, and mitochondrial polarization was associated with enhanced survival and function in mature NKDim cells, including memory-like human cytomegalovirus-dependent CD57+NKG2C+ subsets. In contrast, patients with genetic defects in mitochondrial fusion had a deficiency in adaptive NK cells, which had poor survival in culture. These results support mitochondrial polarization as a central regulator of mature NK cell fitness.

Domaines: Immunologie

Laura Surace, Jean-Marc Doisne, Pedro Escoll, Solenne Marie, Valerie Dardalhon, et al.. Polarized mitochondria as guardians of NK cell fitness. Blood Advances, 2021, 5 (1), pp.26-38. ⟨10.1182/bloodadvances.2020003458⟩. ⟨pasteur-03162799⟩