Adaptive NK cells

Adaptive natural killer (NK) cells or memory-like NK cells is sub-population of differentiated specialized natural killer cells that have the potential to form immunological memory. Adaptive NK cells have been identified in both humans and mice.^[1][2] The term adaptive NK cells stems from their described immunological behaviour, which parallels functions of the adaptive immune system including dynamic expansions of defined subsets of cells^[3] and protective memory responses.^[4] Persistent memory-like NK populations have been reported during viral infection, contact hypersensitivity reactions, and after stimulation by pro-inflammatory cytokines or activating receptor pathways.^[5] Memory-like NK cells show a diversity of functional, phenotypic, epigenetic, and homeostatic differences from cytotoxic NK (cNK) cells that prove their classification as a separate subset from cNK cells.^[6] This so-called memory-like functionality is antigen-unspecific and characterized by an increased proliferative capacity, long-term persistence in vivo for up to 3 months, and high IFN-γ production and potent cytotoxic activity upon ex vivo restimulation.^[5]

The spectrum of human NK cell diversity is wide due to the variety of the surface receptor, intracellular signaling molecule, expression of the transcription factor, foreign antigen exposure and tissue-specific imprinting.^[1] Besides the direct effects of cytokines on NK cell activation, pre-activation by IL- 12 and IL-18 plus IL-15 can contribute to the development of murine and human NK cells with long-lasting enhanced NK cell functionality even after termination and in the absence of the initial stimulus.^[5] Similar to cytokine-induced memory-like NK cells, CD16 pre-activated NK cells up-regulate CD25 expression particularly in the presence of IL-12, resulting in increased sensitivity to low-dose IL-2 and more vigorous proliferation and expansion in response to IL-2.^[5]

Human adaptive NK cells are likely to be derive from cNK cells in peripheral blood.^[1] In particular, CD56dim cNK cells can be a probable pool of progenitor cells for adaptive NK cells.^[1] The reason is that CD56dim cNK cells are more likely to express KIRs and/or CD94/NKG2C.^[1] These surface molecules in turn can transmit important antigen-sensing signals during infection.^[1] CD49a+NKG2C+ NK cells are the small populations of HCVM-associated human liver-resident NK cells.^[7] These cells differ from the predominant population of liver-derived CD49e−CD49a− NK cells and increase the possibility that the former constitute a unique tissue-resident adaptive NK cell population in humans.^[7]

Signals transmitted through the IL-12 receptor combined with CD2 and MHC class I-binding receptor provide a three-prong stimulation responsible for promoting the epigenetic and phenotypic modifications that occur in association with adaptive NK cell differentiation.^[8]

NK cells essentially "remember" the previous effects of cytokines.^[5] NK cells pre-activated by IL-12/15/18 transfer their enhanced IFN-γ producing capacity to daughter cells.^[5] HCMV-associated NKG2C+ adaptive NK cells and IL-12/15/18 pre-activated NK cells have been detected to have an epigenetic imprint, for instance, the demethylated CNS1 region of the IFNG gene, which in turn can lead to a remarkable stability of the IFN-γ-producing phenotype even after adoptive transfer.^[5] Both IL-12 and IL-18 are required for the pronounced demethylation of the CNS1 region, whereas IL-15 might serve as a survival factor.^[5]

In addition to the IFNG gene, NKG2C+ adaptive NK cells also showed CpG demethylation of the PRDM1/BLIMP1 and ZBTB32/TZFP genes or hypermethylation of FCER1G (Fc fragment of IgE receptor Ig).^[5] Pre-activation of NK cells by the cytokines IL-12/18 plus IL-15 or by engagement of FcγRIII/CD16 via therapeutic antibodies can induce similar memory-like functions: an enhanced proliferative capacity toward IL-2 due to CD25 up-regulation as well as a strengthened responsiveness to restimulation by tumor cells.^[5] Importantly, both memory-like functionalities are antigen-unspecific and mean “remembering” a previous state of increased activation caused by cytokine exposure or stimulation via activating NK cell receptors.^[5]

Unique and expanded adaptive NK cell populations were observed in peripheral blood in humans that have been previously infected with Human Cytomegalovirus (HCMV).^[9] These NK cells bear activating MHC class I-binding receptors, typically CD94/NKG2C,^[9] demonstrate reduced activation and degranulation in response to activated autologous T cells^[6] and they are CD56dim CD16+.^[1]

In comparison to CD56dim cNK cells, adaptive NK cells generally show decreased expression of surface CD7, CD161, NKp30, NKp46, and SIGLEC-7 but demonstrate retained or even higher expression of CD2, CD57, and CD85j (ILT2, LILRB1).^[1] None of these surface marker expression patterns are inherently specific for adaptive NK cells, but together they may help to identify discrete populations of adaptive NK cells.^[1] Human adaptive NK cells have the hypomethylated region of IFN-γ promoter. After stimulation through CD16 ligation adaptive NK cells produce large amounts of IFN-γ and also extensively proliferate.^[9] The cytotoxicity of adaptive NK cells remains a constant question in this field. It had been indicated similar or redused degranulation of CD107a as compared to cNK cells after CD16 ligation or stimulation with antibody-coated tumor targets.^[9]

The discovery of memory in the human NK compartment makes us wonder whether it could be harnessed by vaccination. This could be particularly effective in HIV infections where CD4+T cells get rapidly depleted as it provides an alternative where B and T cells cannot be harnessed.^[10]

The clinical application of NK cells with memory-like properties can significantly increase the efficiency of these cells and pave the way for the new NK cell-based clinical approaches for the cancer treatment.^[11] Adaptive NK cells can mediate the enhanced antitumor effects, that may be due to their increased cytotoxicity, high IFN-γ production capacity, and persistence in large numbers in the host.^[11]

Clinical use of allogeneic NK cells is promising for the treatment of leukemia.^[11] KIR-ligand mismatch has a beneficial effect on the alloreactivity of donor NK cells against recipient leukemia.^[11] Besides, it has been shown that the adoptive transfer of alloreactive NK cells does not cause graft-versus-host disease (GVHD), but instead suppresses GVHD.^[11]

• Killer-cell immunoglobulin-like receptor
• KLRC2
• Adoptive cell transfer
• CD56
• Human Cytomegalovirus
• IFN-γ

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