6.3.1 Development and Function Maturation of NK Ce...
In human, the primary organ where NK cells mature is still under active investigation.There is ample evidence that NK cells can mature from the lymph nodes (LNs).Lin-CD34+ hematopoietic stem cells (HSCs) differentiate into CD45RA+ lymphoid-primed multipotential progenitor (LMPP).By expressing CD38, CD7, CD10, and the cytokine receptor CD127 (IL-7 receptor-alpha), LMPPs transition into common lymphoid progenitors (CLPs) that have the potential to make lineage commitment into Pro-B, Pre-T, NK cell progenitors (NKPs), or other innate lymphoid cells.Expression of CD122 (IL-2Rβ) marks the irreversible fate decision of CLPs into NK lineage.The appearance of CD56 (neural cell adhesion molecule) indicates a final transition of immature NK cell (iNK) into mature NK cells.Most of the iNK cells transition into a minor CD56 bright population (-5%) that convert into major CD56 dim (＞90%) population.It is also suggested that iNK cells can directly give rise to CD56 dim population (dotted arrow) that is yet to be validated(Figure 6.6) [77].
Figure 6.6 Devel opmental origin of human natural killer (NK) cel ls.In human, the primary organ where NK cells mature is still under active investigation.There is ample evidence that NK cells can mature from the lymph nodes (LNs).Lin-CD34+ hematopoietic stem cells (HSCs) differentiate into CD45RA+ lymphoid-primed multipotential progenitor (LMPP).By expressing CD38, CD7, CD10, and the cytokine receptor CD127 (IL-7 receptor-alpha), LMPPs transition into common lymphoid progenitors (CLPs) that have the potential to make lineage commitment into Pro-B, Pre-T, NK cell progenitors (NKPs), or other innate innate lymphoid cells.Expression of CD122 (IL-2Rβ) marks the irreversible fate decision of CLPs into NK lineage.The appearance of CD56 (neural cell adhesion molecule) indicates a final transition of immature NK cell (iNK) into mature NK cells.Most of the iNK cells transition into a minor CD56bright population (～5%) that convert into major CD56dim (＞90%)population.It is also suggested that iNK cells can directly give rise to CD56dim population (dotted arrow)that is yet to be validated.
Source: Abel A M, Yang C, Thakar M S, Malarkannan S.“Natural killer cells: Development, maturation,and clinical utilization”.FrontiersinImmunology, 2018, 9:1869.
A total of six distinct developmental stages have been described with Stages 2 and 4 having additional bifurcations.Similar with the mouse, human NK cells express CD244 (2B4) throughout the developmental process starting at Stage 1 (pre-NK cell precursors).CD117 (c-Kit) and the low levels of interleukin (IL)-1R1 expressions define the Stage 2a and Stage 2b, respectively (NK cell progenitors).A higher expression of IL-1R1 defines the Stage 3 [immature NK cell (iNK)], and the expressions of NKG2D, CD335 (NKp46), CD337 (NKp30), and CD161 (NK1.1) are initiated.Stages 4a and 4b defines an entry of iNKs into mature nks, and are differentiated by the expression of NKp80 at the Stage 4b.Expressions of NKG2D, CD335, CD337, and CD161 reach their maximal levels at Stage 4.Most important of all, CD56 expression peaks (CD56 bright).Significant differences between Stage 4b and Stage 5 are defined by a decrease in the expression of CD56 (CD56dim) in most and initiation of the expression of CD16 (FcγRIIIA) and killer immunoglobulin-like receptor (KIR) (CD158) in a subset of NK cells.Stage 6 defines the generation of “adaptive” or “memory-like” NK cells following “antigen” exposure, and it is identified by the high levels of NKG2C [77].(https://www.daowen.com)
The common gamma chain-containing receptor family consists of six members, interleukin (IL)-2R,IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R.Each one of them is distinguished from others by their unique α-chains.IL-2Rβ is shared by IL-2R and IL-15R complexes.In mouse, NK cell progenitors(NKPs) utilize IL-7R early during their transition from Pre-NKPs into refined-NKPs.In human,apart from its role in the early development, IL-7 also regulates the survival and expansion of mature CD56 Bright NK cells.IL-15R and IL-21R are required by NK cells to initiate and sustain their proliferation.Although it has been widely used to expand human and mouse NK cells ex vivo,the in vivo role of IL-2 that is primarily produced by CD4+ T cells is yet to be better understood.Role of IL-4 and IL-9 in NK cell development is less explored.Distinct sets of Janus kinases (JAK)and signal transducers and activators of transcription (STAT) associate and transmit the signaling from the common gamma chain-associated cytokine receptors (Figure 6.7) [77].
Figure 6.7 Rol e of common gamma-containing receptors in natura l killer (NK) cell development.The common gamma chain-containing receptor family consists of six members, interleukin (IL)-2R,IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R.Each one of them is distinguished from others by their unique α-chains.IL-2Rβ is shared by IL-2R and IL-15R complexes.In mouse, NK cell progenitors(NKPs) utilize IL-7R early during their transition from Pre-NKPs into refined-NKPs.In human, apart from its role in the early development, IL-7 also regulates the survival and expansion of mature CD56bright NK cells.IL-15R and IL-21R are required by NK cells to initiate and sustain their proliferation.Although it has been widely used to expand human and mouse NK cells ex vivo, the in vivo role of IL-2 that is primarily produced by CD4+ T cells is yet to be better understood.Role of IL-4 and IL-9 in NK cell development is less explored.Distinct sets of Janus kinases (JAK) and signal transducers and activators of transcription (STAT) associate and transmit the signaling from the common gamma chain-associated cytokine receptors.(Please scan the QR code on the Preface to get original color figures.)
Source: Abel A M, Yang C, Thakar M S, Malarkannan S.“Natural killer cells: Development, maturation,and clinical utilization”.FrontiersinImmunology, 2018, 9:1869.
Natural killer cells do not express clonotypic receptors.However, they mediate strong anti-tumor cytotoxicity and generate significant quantities of pro-inflammatory cytokines.Lack of variable clonotypic receptors is compensated by multiple germline-encoded NK cell activation receptors(NKRs) such as NKG2D, NCR1, NCR2, NCR3, NKG2C, CD244, Ly49D, and Ly49H.Expression of more than one NKR that recognize self or pathogen-derived ligands endows NK cells with inherent, innate abilities to mediate effector functions.Due to the expression of multiple activation receptors, NK cells have to follow a distinct developmental program to obviate misrecognition of“self” leading to autoimmune responses.The varied nature of NKRs and the absence of signaling domains in their cytoplasmic tails necessitates the association and recruitment of receptor associated adaptor molecules for signal transduction.However, Ly49H and NKG2D can also signal via the YINM motif present within the adaptor, DAP10.NK cell activation through these receptors occurs by interacting with distinct cellular and foreign ligands present on diseased cells and form the basis for the NK cell-mediated immune response in multiple contexts [78-82].