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]


Origin

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]

Epigenetic regulation

NK cells essentially "remember" the previous effects of cytokines.[5] NK cells pre-activated by IL-12/15/18 transfer their enchanced 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]

In humans

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]

Therapeutic potential

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.[10] 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.[10]

Clinical use of allogeneic NK cells is promising for the treatment of leukemia.[10] KIR-ligand mismatch has a beneficial effect on the alloreactivity of donor NK cells against recipient leukemia.[10] 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.[10]

See also

References
  1. Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA (November 2017). "The Broad Spectrum of Human Natural Killer Cell Diversity". Immunity. 47 (5): 820–833. doi:10.1016/j.immuni.2017.10.008. PMC 5728700. PMID 29166586.
  2. Hammer Q, Romagnani C (Nov 30, 2016). "About Training and Memory: NK-Cell Adaptation to Viral Infections". Advances in Immunology. 133: 171–207. doi:10.1016/bs.ai.2016.10.001. PMID 28215279.
  3. Béziat V, Liu LL, Malmberg JA, Ivarsson MA, Sohlberg E, Björklund AT, et al. (April 2013). "NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs". Blood. 121 (14): 2678–88. doi:10.1182/blood-2012-10-459545. PMC 3617633. PMID 23325834.
  4. Sun JC, Beilke JN, Lanier LL (January 2009). "Adaptive immune features of natural killer cells". Nature. 457 (7229): 557–61. doi:10.1038/nature07665. PMC 2674434. PMID 19136945.
  5. Pahl JH, Cerwenka A, Ni J (2018). "Memory-Like NK Cells: Remembering a Previous Activation by Cytokines and NK Cell Receptors". Frontiers in Immunology. 9: 2796. doi:10.3389/fimmu.2018.02796. PMC 6279934. PMID 30546366.
  6. Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V, Holmes TD, et al. (March 2015). "Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function". Immunity. 42 (3): 443–56. doi:10.1016/j.immuni.2015.02.008. PMC 4612277. PMID 25786176.
  7. Stegmann KA, Robertson F, Hansi N, Gill U, Pallant C, Christophides T, et al. (May 2016). "CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver". Scientific Reports. 6: 26157. doi:10.1038/srep26157. PMC 4876507. PMID 27210614.
  8. Hammer Q, Romagnani C (2017). "About Training and Memory: NK-Cell Adaptation to Viral Infections". Advances in Immunology. 133: 171–207. doi:10.1016/bs.ai.2016.10.001. PMID 28215279.
  9. Lee J, Zhang T, Hwang I, Kim A, Nitschke L, Kim M, et al. (March 2015). "Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals". Immunity. 42 (3): 431–42. doi:10.1016/j.immuni.2015.02.013. PMC 4537797. PMID 25786175.
  10. Peng H, Tian Z (2017-09-13). "Natural Killer Cell Memory: Progress and Implications". Frontiers in Immunology. 8: 1143. doi:10.3389/fimmu.2017.01143. PMC 5601391. PMID 28955346.
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