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From immunogenetic polymorphism to functional antitumor lymphocyte mitochondrial dynamics

The major histocompatibility complex and the leukocyte receptor complex are the two most polymorphic regions of the immune genome. Individuals with increasingly diverse repertoires of MHC class-I molecules have a greater potential for their natural killer (NK) cells to be more responsive. NK cell activity is under complex regulation of NK cell education that is fine-tuned by tumor microenvironment. NK cells with a greater number of inhibitory receptors that recognize the surrounding MHC class-I respond to stimuli better than NK cells with less recognition of the surrounding MHC. We investigated the mechanisms of local tumor antigen-specific T cell-NK cell collaboration, which appeared indispensable for the elimination of tumor cells, including antigen-deficient tumor escape variants that arise before metastasis. We observed in a mouse model of mastocytoma expressing a self-tumor-antigen P1A that effector CD8T cells provided a necessary “help” to dormant NK cells in eliciting their antitumor effector function. Bioluminescence imaging of mastocytoma tumors following adoptive transfer of P1A-specific T cells in RAG-/- and RAG-/-γc-/- mice showed that NK cell anti-tumor activity requires cytolytic T cells, whereas T cells can function independent of NK cells. In 2D and 3D co-culture systems, we observed that PMA/ionomycin-stimulated CD8T cells form multiple contacts with naïve NK lymphocytes. Data show that NK cells interacting with activated CD8T cells show an up-regulation of CD25 and CD69 expression mediated by intercellular contacts, and activation of NKG2D receptors and Stat2, Stat6, Jak1, Jak3, Tyk2, and PTEN signaling molecules with a decrease in the phosphorylation of Stat1, PKB/Akt, SAPK/JNK, p38. On the other hand, interacting NK cells down-regulate CD25 molecule expression on CD8T cells and promote differentiation of central-memory CD44+CD62L+T cells. CD8T cells display an elevation in the phosphorylation of Stat1 and down-regulation of Stat5 with stimulated PKB/Akt, Lck, mTOR, and p42/p44. Alterations in phosporylation status of multiple signaling proteins during CD8T–NK interaction suggest a cellular remodelling, whereby NK cells polarize activated CD8T cells towards a central-memory phenotype and activated CD8T lymphocytes induce naive NK cells towards effector/regulatory phenotype. Moreover, significant changes in the cytosolic and mitochondrial Ca2+, production of mitochondrial ROS, mitochondrial membrane potential, mitochondrial permeability transition pore, and synthesis of nitric oxide and non-protein thiols (mostly, reduced glutathion) were observed in a reciprocal CD8T–NK interaction. These findings highlight the importance of mitochondrial activity in the re-modeling of activation signaling and memory differentiation of interacting CD8T cells and NK cells, with a potential to refine cancer immunotherapeutic strategies.

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Correspondence to Anil Shanker.

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Keywords

  • Natural Killer
  • Natural Killer Cell
  • Mitochondrial Permeability Transition Pore
  • CD8T Cell
  • Leukocyte Receptor Complex