Polarized mitochondria as guardians of NK cell fitness

Abstract

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.

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“…CD56 bright NK cells are the major producers of cytokines including IFN-γ (interferon-γ) and TNF-α (tumour necrosis factor-α), while CD56 dim NK cells primed for cytotoxicity with high expression of the cytotoxic machinery. CD56 dim NK cells purified directly from human peripheral blood mononuclear cells (PBMC) at steady state have higher rates of glycolysis and OXPHOS and increased mitochondrial mass when compared to CD56 bright NK cells [ 9 ]. There is also some evidence that human NK cells from blood and tissues such as the spleen and liver have different metabolic profiles [ 11 ].…”

“…Various combinations of cytokines upregulate glycolysis and OXPHOS in murine NK cells that are accompanied by increased expression of key nutrient transporters, glycolytic enzymes, increased mitochondrial mass and metabolic fluxes [ 12 – 15 ]. Similarly, in human NK cells isolated from PBMC, 18-h stimulation with cytokines including IL2, IL12+IL15 or IL12+IL15+IL18 results in increased expression of nutrient receptor expression and enhanced glycolytic flux [ 9 , 16 ]. More recently, studies have shown IL-21 expanded human NK cells have significantly elevated basal and maximal glycolysis but downregulated OXPHOS compared to peripheral blood NK cells.…”

“…There are differences in how human CD56 bright and CD56 dim NK cells modulate mitochondrial functions following cytokine stimulation. While CD56 bright NK cells increase mitochondrial mass, mitochondrial polarisation and OXPHOS in response to stimulation, under the same conditions, CD56 dim NK cells show decreases in these mitochondrial parameters [ 9 ]. These decreases in mitochondrial function are very pronounced in CD56 dim NK cells stimulated with IL12+IL15+IL18 [ 9 ] but less so in response to other cytokine combinations (unpublished data).…”

“…While CD56 bright NK cells increase mitochondrial mass, mitochondrial polarisation and OXPHOS in response to stimulation, under the same conditions, CD56 dim NK cells show decreases in these mitochondrial parameters [ 9 ]. These decreases in mitochondrial function are very pronounced in CD56 dim NK cells stimulated with IL12+IL15+IL18 [ 9 ] but less so in response to other cytokine combinations (unpublished data). Interestingly, interventions that preserve the mitochondrial functions of CD56 dim NK cells appear to increase the longevity of these cells [ 9 ].…”

“…These decreases in mitochondrial function are very pronounced in CD56 dim NK cells stimulated with IL12+IL15+IL18 [ 9 ] but less so in response to other cytokine combinations (unpublished data). Interestingly, interventions that preserve the mitochondrial functions of CD56 dim NK cells appear to increase the longevity of these cells [ 9 ]. Indeed, these data fit with an emerging narrative that maintaining mitochondrial fitness is an essential metabolic requirement for prolonged lymphocyte responses.…”