Defining Early Human NK Cell Developmental Stages in Primary and Secondary Lymphoid Tissues

Abstract

A better understanding of human NK cell development in vivo is crucial to exploit NK cells for immunotherapy. Here, we identified seven distinctive NK cell developmental stages in bone marrow of single donors using 10-color flow cytometry and found that NK cell development is accompanied by early expression of stimulatory co-receptor CD244 in vivo. Further analysis of cord blood (CB), peripheral blood (PB), inguinal lymph node (inLN), liver lymph node (liLN) and spleen (SPL) samples showed diverse distributions of the NK cell developmental stages. In addition, distinctive expression profiles of early development marker CD33 and C-type lectin receptor NKG2A between the tissues, suggest that differential NK cell differentiation may take place at different anatomical locations. Differential expression of NKG2A and stimulatory receptors (e.g. NCR, NKG2D) within the different subsets of committed NK cells demonstrated the heterogeneity of the CD56 bright CD16 +/2 and CD56 dim CD16 + subsets within the different compartments and suggests that microenvironment may play a role in differential in situ development of the NK cell receptor repertoire of committed NK cells. Overall, differential in situ NK cell development and trafficking towards multiple tissues may give rise to a broad spectrum of mature NK cell subsets found within the human body.

Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

“…However, this is only based on the expression pattern of CD56 and CD16 (18)(19)(20)(21)(22). Our data provide evidence that ltNK cells are not just a subpopulation of either of the conventional NK cell populations.…”

“…Data obtained from murine experiments indicate that lymphoid tissues are the primary site for cellular interactions between NK cells and other immune cells (4)(5)(6). In humans, CD56 bright NK cells are enriched in marrow and spleen and make up the vast majority of mature NK cells in lymph node (18)(19)(20)(21)(22). Still, the mechanisms involved in the localization of human NK cells in lymphoid organs are largely unknown.…”

Multifunctional human CD56low CD16low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients

“…25,26 Unlike the well-defined stages of BM NK-cell development in the mouse, in humans the information on NK-cell development in BM is rather limited. Indeed, while four NK-cell developmental intermediates have been described, both phenotypically and functionally, in human lymph nodes and tonsils, 25,27 no evidence on the effector functions of the four different NK-cell subsets so far reported in the BM 28 and their relation to the PB counterpart has been provided.…”

Functional and immunophenotypic characteristics of NK cells from regional lymph nodes of melanoma patients and their in vitro activation with IL-2 and IL-15

“…S obzirom da je pokazano njegovo prisustvo i na subpopulacijama dendritičnih ćelija koje imaju citotoksični potencijal, u novije vreme CD56 antigenu se pripisuje uloga u citotoksičnoj funkciji mada njegova uloga u tom procesu nije do sada u potpunosti definisana (Roothans et al, 2013 (Freud et al, 2006;Mujaj et al, 2011;Eissens et al, 2012).…”

“…U stadijumu pre-NK ćelija dolazi do pojave β subjedinice (interleukin-2) IL-2 i (interleukin-15) IL-15 receptora (IL-2/15Rβ) CD122, čime ove ćelije postaju osetljive na citokin IL-15 koji uslovljava njihov dalji razvoj i na IL-2, koji sa IL-15 ima zajednički β lanac receptora (Freud et al, 2006;Eissens et al, 2012 aktivacionog receptora i KIR receptora kao i povećanje nivoa citotoksičnog medijatora perforina (Freud et al, 2005;. Ekspresija gena za KIR receptore je suprimirana u manje zrelim razvojnim stadijumima (Chan et al, 2003;2005;Cichocki et al, 2011), a KIR receptori se u procesu razvoja NK ćelija pojavljuju istovremeno sa granulama ispunjenim citotoksičnim medijatorima (perforin i granzimi).…”