NK Cell Development in Times of Innate Lymphoid Cell Diversity

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.

Specific Patterns of Blood ILCs in Metastatic Melanoma Patients and Their Modulations in Response to Immunotherapy

“…Recently, NK cells were classified in the family of innate lymphoid cells (ILCs), which gather cytotoxic effectors (NK cells) and helper-type ILCs (h-ILCs) [ 20 ]. The h-ILCs arise from a common lymphoid progenitor [ 21 , 22 ] and are located in mucosal barriers and various tissues [ 23 ], including the intestine, skin, lung, and adipose tissue [ 24 ]. ILCs are heterogeneous subsets of lymphocytes that have emerging roles in orchestrating immune response and contribute to maintaining homeostasis and regulating tissue inflammation [ 25 ].…”

Innate lymphoid cell subsets and their cytokines in autoimmune diseases

“…ILCs in Group 3 use RORC to produce IL-17 and IL-22 (TH17-related cytokines) [14][15][16][17]. Hematopoietic stem cells (HSCs) give rise to all the different blood cell progenitors, among which common lymphoid progenitors (CLPs) are precursors of all the ILC subtypes as well as B cells and T cells [18,19]. Recently, an early ILC progenitor, also known as the common innate lymphoid progenitor (CILP), was identified as CXCR6+ cells within the aLP population [20].…”

“…In addition, lymphoid tissue inducer (LTi) cells as well as CD4+ T-cells can be derived directly from CHILP [6]. Cells with a high level of PLZF (promyelocytic leukemia zinc finger protein) and a4b7/Lin-/IL-7Ra+/cKit+ and CXCR6-are defined as the innate lymphoid cell progenitor (ILCP) population that originates from the CHILP [19]. Recently it has been shown that both cytotoxic and helper ILCs can be derived from RORgt+ ILCPs [23].…”

NK cells at the crossroads in COVID-19: a question of timing

“…The NK cell component of this system is comprised of about 2 to 18% of the lymphocytes in peripheral blood (Vivier et al, 2008 as members of the innate lymphoid cell (ILC) family, that are primarily characterized by their ability to kill target cells. (Stokic-Trtica et al, 2020). This cytotoxic activity is regulated by the "missing self" postulate (Ljunggren & Kärre, 1990).…”