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Review
. 2020 Jul 8:11:813.
doi: 10.3389/fimmu.2020.00813. eCollection 2020.

NK Cell Development in Times of Innate Lymphoid Cell Diversity

Vladislava Stokic-Trtica  1   2 , Andreas Diefenbach  1   3   4 , Christoph S N Klose  1
Affiliations
Review

NK Cell Development in Times of Innate Lymphoid Cell Diversity

Vladislava Stokic-Trtica et al. Front Immunol. .

Abstract

After being described in the 1970s as cytotoxic cells that do not require MHC-dependent pre-activation, natural killer (NK) cells remained the sole member of innate lymphocytes for decades until lymphoid tissue-inducer cells in the 1990s and helper-like innate lymphoid lineages from 2008 onward completed the picture of innate lymphoid cell (ILC) diversity. Since some of the ILC members, such as ILC1s and CCR6- ILC3s, share specific markers previously used to identify NK cells, these findings provoked the question of how to delineate the development of NK cell and helper-like ILCs and how to properly identify and genetically interfere with NK cells. The description of eomesodermin (EOMES) as a lineage-specifying transcription factor of NK cells provided a candidate that may serve as a selective marker for the genetic targeting and identification of NK cells. Unlike helper-like ILCs, NK cell activation is, to a large degree, regulated by the engagement of activating and inhibitory surface receptors. NK cell research has revealed some elegant mechanisms of immunosurveillance, coined "missing-self" and "induced-self" recognition, thus complementing "non-self recognition", which is predominantly utilized by adaptive lymphocytes and myeloid cells. Notably, the balance of activating and inhibitory signals perceived by surface receptors can be therapeutically harnessed for anti-tumor immunity mediated by NK cells. This review aims to summarize the similarities and the differences in development, function, localization, and phenotype of NK cells and helper-like ILCs, with the purpose to highlight the unique feature of NK cell development and regulation.

Keywords: NK cells; immune receptor; immune recognition; innate lymphocytes; innate lymphoid cells.

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Figures

Figure 1
Figure 1
Principles of immune recognition. The immune system constantly senses the presence or absence of “self” and “non-self” molecules by stimulatory and inhibitory receptors. Activation of immune cells is triggered by the direct recognition of microbial “non-self,” “missing-self” recognition, or “induced-self” recognition (illustrations were created with BioRender.com).
Figure 2
Figure 2
Progenitor commitment to innate lymphoid cells (ILCs). Schematic representation of progenitor populations with various differentiation potentials toward ILCs. The common lymphoid progenitor (CLP) gives rise to B-cells, T cells, and ILCs. The early innate lymphoid progenitors (26) possess the potential for NK cells, ILC1s, ILC2s, and ILC3s, whereas CHILP-A (21) and CHILP-B (98) possess the potential for ILC1s, ILC2s, and ILC3s as indicated. In square brackets are the population-defining markers reported in the literature. The transcription factors required for the indicated lineage or transition from one population to another are indicated within the cells or on the arrows, respectively (illustrations created with BioRender.com).
Figure 3
Figure 3
Development of NK cells and ILC1s. (A) Developmental stages of murine conventional NK cells. Representation of markers used for the identification of individual developmental stages. Markers highlighted in red represent those expressed mainly in the given subset and therefore important for its identification. At each stage, the expression of the listed markers is depicted as “+”, whereas the absence of expression is indicated by “–” or alternatively “low.” (B) Tissue-specific non-conventional NK/ILC1 subsets. Representation of markers used for the identification of non-conventional/ILC1 subsets in thymus, intestine, and liver (illustrations created with BioRender.com).
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