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]

## Contents

* 1 Origin
* 2 Epigenetic regulation
* 3 In humans
* 4 Therapeutic potential
* 5 See also
* 6 References

## 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 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]

## 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]

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]

## 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.[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]

## See also

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

## References

1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "The Broad Spectrum of Human Natural Killer Cell Diversity". Immunity 47 (5): 820–833. November 2017. doi:10.1016/j.immuni.2017.10.008. PMID 29166586.
2. ↑ "About Training and Memory: NK-Cell Adaptation to Viral Infections". Advances in Immunology 133: 171–207. Nov 30, 2016. doi:10.1016/bs.ai.2016.10.001. PMID 28215279.
3. ↑ "NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs". Blood 121 (14): 2678–88. April 2013. doi:10.1182/blood-2012-10-459545. PMID 23325834.
4. ↑ "Adaptive immune features of natural killer cells". Nature 457 (7229): 557–61. January 2009. doi:10.1038/nature07665. PMID 19136945.
5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 "Memory-Like NK Cells: Remembering a Previous Activation by Cytokines and NK Cell Receptors" (in English). Frontiers in Immunology 9: 2796. 2018. doi:10.3389/fimmu.2018.02796. PMID 30546366.
6. ↑ 6.0 6.1 "Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function". Immunity 42 (3): 443–56. March 2015. doi:10.1016/j.immuni.2015.02.008. PMID 25786176.
7. ↑ 7.0 7.1 "CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver". Scientific Reports 6: 26157. May 2016. doi:10.1038/srep26157. PMID 27210614.
8. ↑ "About Training and Memory: NK-Cell Adaptation to Viral Infections". Advances in Immunology 133: 171–207. 2017. doi:10.1016/bs.ai.2016.10.001. PMID 28215279.
9. ↑ 9.0 9.1 9.2 9.3 "Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals". Immunity 42 (3): 431–42. March 2015. doi:10.1016/j.immuni.2015.02.013. PMID 25786175.
10. ↑ Perera Molligoda Arachchige, Arosh Shavinda (2021-03-24). "Human NK cells: From development to effector functions." (in en). Innate Immunity: 17534259211001512. doi:10.1177/17534259211001512. ISSN 1753-4259. https://doi.org/10.1177/17534259211001512.
11. ↑ 11.0 11.1 11.2 11.3 11.4 "Natural Killer Cell Memory: Progress and Implications". Frontiers in Immunology 8: 1143. 2017-09-13. doi:10.3389/fimmu.2017.01143. PMID 28955346.

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