Journal
BLOOD ADVANCES
Volume 5, Issue 1, Pages 26-38Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2020003458
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Funding
- Agence Nationale de la Recherche [ANR-10-INSB-04-01]
- INSERM
- Institut Pasteur
- Agence Nationale de le Recherche [ANR-10-LABX-62-IBEID, ANR-10-LABX-73REVIVE]
- European Research Council [695467]
- Fondation pour la Recherche Medicale [EQU201903007847]
- Swiss National Science Foundation Early Postdoctoral Mobility fellowship
- Marie Curie grant [H2020-MSCA-IF-2017]
- EU [765104]
- European Union [665807]
- European Research Council (ERC) [695467] Funding Source: European Research Council (ERC)
- Marie Curie Actions (MSCA) [765104] Funding Source: Marie Curie Actions (MSCA)
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This study revealed that different subsets of NK cells exhibit varied responses in mitochondrial dynamics upon activation, highlighting the central role of mitochondrial polarization in regulating NK cell function.
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 CD56(Dim) (NKDim) cells have fused mitochondria and enhanced metabolism compared with CD56(Br) (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-gamma 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.
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