The Abundant NK Cells in Human Secondary Lymphoid Tissues Require Activation to Express Killer Cell Ig-Like Receptors and Become Cytolytic

Abstract

Natural killer cells are important cytolytic cells in innate immunity. We have characterized human NK cells of spleen, lymph nodes, and tonsils. More than 95% of peripheral blood and 85% of spleen NK cells are CD56dimCD16+ and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs). In contrast, NK cells in lymph nodes have mainly a CD56brightCD16− phenotype and lack perforin. In addition, they lack KIRs and all NCR expression, except low levels of NKp46. The NK cells of tonsils also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 and NKp46. Upon IL-2 stimulation, however, lymph node and tonsilar NK cells up-regulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL-2 activation, and therefore display a phenotype similar to peripheral blood NK cells. We hypothesize that IL-2 can mobilize the NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. Because lymph nodes harbor 40% and peripheral blood only 2% of all lymphocytes in humans, this newly characterized perforin− NK cell compartment in lymph nodes and related tissues probably outnumbers perforin+ NK cells. These results also suggest secondary lymphoid organs as a possible site of NK cell differentiation and self-tolerance acquisition.

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…These cells are retained in the tissues through their expression of CD69, chemokine receptors such as CXCR6 and CCR5, as well as adhesion molecules such as CD49a. For example, more than 75% of the NK cells in lymph nodes express CD56 at high levels,52, 105 the majority of which express CD69 and CXCR6, and have been shown to be lymphoid tissue‐resident 105. Similar enrichment of both tissue‐resident and circulating CD56 bright NK cells has been found in the spleen, bone marrow and tonsils.…”

“…As murine NK cells do not express CD56, RAG2 −/− γ c −/− mice transplanted with human haematopoietic stem cells have been used to show that CD56 bright NK cells differentiated linearly into CD56 dim NK cells, acquiring CD16 and KIR expression 65, 66. This has also been shown in vitro by culturing CD56 bright NK cells in the presence of synovial or skin fibroblasts, or cytokines 52, 67…”

“…For example, the CD56 bright NK cell population can kill activated autologous CD4+ T‐cells in MS 101, 102. Furthermore, immature DCs are killed by CD56 bright NK cells in lymph nodes in a TRAIL‐dependent manner,103, 104 and IL‐2‐activated peripheral blood CD56 bright NK cells can become efficient killers 50, 51, 52. Similarly, CD69 + CXCR6 + tissue‐resident CD56 bright NK cells in lymphoid tissues have recently been shown to constitutively express perforin, but require pre‐activation to express GrB and become cytotoxic,105 much like MAIT cells.…”

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

“…Although these results provide direct evidence that a transition of CD56 bright to CD56 dim may occur, it remains unclear to what extent this transition represents the typical differentiation pathway in vivo. Furthermore, the fact that CD56 bright may acquire many features of CD56 dim may not be ground enough to denote them as less mature or as CD56 dim precursors, not only because they largely outnumber CD56 dim [5,6] [29,31,32,34]. In this study, we have compared NK cells at an early stage after graft take (defined as the first of two consecutive days that the transplanted HSC produced 40.5 Giga per liter (G/L) of granulocytes) with cytokine-stimulated CD56 bright from peripheral blood of normal controls.…”

“…This definition now seems imprecise. NK cells are very heterogeneous and the cytokine-producing CD56 bright that lack cytotoxic capability largely outnumber NK cells exerting natural cytotoxicity [5,6]. During maturation, pre-NK cells and iNK express high levels of CD56 [18,19].…”