BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory

Abstract

SUMMARY Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived “memory” cells, processes poorly understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS)-dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to-memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes.

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

“…50 Sun and colleagues recently demonstrated a role for mitophagy in protecting MCMV-specific memory NK cells from apoptosis. 28 We show that in donor NK cells from mice with GVHD, autophagy is exaggerated, which likely accounts for the accumulation of dysfunctional mitochondria also observed in this setting. We also show that treatment with IL-15 complexes rescues the NK-cell defect in an autophagy-dependent manner.…”

“…Autophagy of dysfunctional/ damaged mitochondria, termed mitophagy, is a process that occurs in memory NK cells to promote their survival. 28 We used 3 cellular stains to interrogate donor NK-cell mitochondrial quality postallogeneic transplant. At day 14, donor NK cells in non-GVHD and GVHD mice expressed equivalent levels of MitoSox Red (measuring mitochondrial-associated reactive oxygen species) in the BM and spleen (Figure 6B left).…”

Natural killer cell memory in infection, inflammation and cancer

“…NK cells deficient in the anti-apoptotic factor BIM (encoded by Bcl2l11) expand normally in response to MCMV infection, but contraction of the LY49H + NK cell pool and functional NK cell memory formation are impaired 60 . More recently, similarly to the mechanisms driving CD8 + T cell memory formation, autophagy was shown to be required for survival of effector NK cells during the contraction phase by an Atg3-dependent mechanism 61 . In future studies, it will be important to determine whether and to what extent unique pathways driving NK cell memory generation exist that differ from CD8 + T cell memory formation.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Recently, it has been discovered that NK cells may undergo memory formation with the generation of antigen-specific NK cells, even though −apparently, only during viral infection and not during cancer development [191]. While during their effector/expansion phase NK cells accumulates high amount of ROS, during the contraction-to-memory phase mitochondrial receptor BNIP3-BNIP3L proteins mediate removal of damaged mitochondria through mitophagy, thus reducing ROS amount and so promoting memory formation [192]. Although it has not been directly investigated whether or not mitochondrial dynamics are involved in this process, Drp1-dependent mitochondrial fission has the potential to play an important role in promoting mitochondrial clearance for the different reasons described above (Fig.…”