On the Way to Become a Natural Killer Cell

Abstract

Natural Killer (NK) cells are innate lymphocytes playing pivotal roles in host defense and immune-surveillance. The homeostatic modulation of germ-line encoded/non-rearranged activating and inhibitory NK cell receptors (NKRs) determines the capability of these innate lymphocytes to either spare “self” cells or to kill viral-infected, tumor-transformed and heterologous cell targets. However, despite being discovered more than 40 years ago, several aspects of NK cell biology remain unknown or are still being debated. In particular, our knowledge of human NK cell ontogenesis and differentiation is still in its infancy as the majority of our experimental evidence on this topic mainly comes from findings obtained in vitro or with animal models in vivo . Although both the generation and the maintenance of human NK cells are sustained by hematopoietic stem cells (HSCs), the precise site(s) of NK cell development are still poorly defined. Indeed, HSCs and hematopoietic precursors are localized in different anatomical compartments that also change their ontogenic commitments before and after birth as well as in aging. Currently, the main site of NK cell generation and maturation in adulthood is considered the bone marrow, where their interactions with stromal cells, cytokines, growth factors, and other soluble molecules support and drive maturation. Different sequential stages of NK cell development have been identified on the basis of the differential expression of specific markers and NKRs as well as on the acquisition of specific effector-functions. All these phenotypic and functional features are key in inducing and regulating homing, activation and tissue-residency of NK cells in different human anatomic sites, where different homeostatic mechanisms ensure a perfect balance between immune tolerance and immune-surveillance. The present review summarizes our current knowledge on human NK cell ontogenesis and on the related pathways orchestrating a proper maturation, functions, and distributions.

NK Cell-Based Immunotherapy in Renal Cell Carcinoma

“…These CLPs further differentiate into NK cell progenitors (NKP) that are classified into three sequential stages of maturation, named NK cell progenitors (stage 1), pre-NK cells (stage 2), and immature NK cells (stage 3). The early stages of NK cell development and differentiation have been characterized in the context of the bone marrow niche, but pre-NK cells can be detected in the circulation, and other data have shown that they are enriched in extramedullary tissues where subpopulations of mature NK cells reside, suggesting that they have developed locally [3,25,31]. It is known that some NKPs are selectively enriched in SLT, such as lymph nodes and tonsils, as well as in the gastrointestinal tract, liver, and uterus [32][33][34][35][36][37].…”

“…It is known that some NKPs are selectively enriched in SLT, such as lymph nodes and tonsils, as well as in the gastrointestinal tract, liver, and uterus [32][33][34][35][36][37]. The most accepted model of NK cell development occurs in the linear fashion just described above, in which the expression of CD94 marks the commitment to the CD56 bright stage (stage 4), that next differentiate into CD56 dim NK cells (stages 5 and 6) [25,31]. The differentiation into adaptive (also called memory) CD56 dim NK cells could subsequently occur after viral infection, as, for example, the human cytomegalovirus [25].…”

“…The most accepted model of NK cell development occurs in the linear fashion just described above, in which the expression of CD94 marks the commitment to the CD56 bright stage (stage 4), that next differentiate into CD56 dim NK cells (stages 5 and 6) [25,31]. The differentiation into adaptive (also called memory) CD56 dim NK cells could subsequently occur after viral infection, as, for example, the human cytomegalovirus [25]. The CD56 neg cells are probably exhausted CD56 dim NK cells, although this has not been well-proven yet [25].…”

“…The differentiation into adaptive (also called memory) CD56 dim NK cells could subsequently occur after viral infection, as, for example, the human cytomegalovirus [25]. The CD56 neg cells are probably exhausted CD56 dim NK cells, although this has not been well-proven yet [25]. Related to the unCD56 dim NK cells, it has been suggested that they are an intermediate stage of differentiation between CD56 bright and CD56 dim NK cells [25].…”

“…The CD56 neg cells are probably exhausted CD56 dim NK cells, although this has not been well-proven yet [25]. Related to the unCD56 dim NK cells, it has been suggested that they are an intermediate stage of differentiation between CD56 bright and CD56 dim NK cells [25]. The support for the linear model comes from analysis of NK cells in SLT and in vitro studies.…”