Approximately, half of the CD56bright in peripheral blood express

Approximately, half of the CD56bright in peripheral blood express CD27, a marker virtually absent from CD56dim13–15. Hence, CD56bright in peripheral blood are identical or closely related

to the NK cells residing in secondary lymphoid organs (SLO) that produce cytokines to guide the adaptive immune response 4–6, 10, 11. It is worth noting that the precise relationship between NK cells in SLO, CD56bright in peripheral blood and CD56dim is not completely understood. Although some of the NK cells in SLO might be CD56bright recirculating from the blood, others could represent early maturation stages of NK cells developing from c-Met inhibitor hematopoietic precursor cells that repopulate extramedullary tissues and retain multi-lineage reconstitution capacity 16. Caligiuri’s group has identified lymphocytes in tonsils and lymph nodes representative of distinct stages of NK-cell development that differentiated into NK cells expressing high levels of CD56 17–19. NK-cell lineage commitment occurred in cells referred to as immature NK cells (iNK) that expressed no, or only very low levels of the NK-cell-associated markers NKp46, CD94, KIR and CD16. Furthermore, they lacked the characteristic attributes of mature NK cells: a high expression of the complement receptor CD11b as well as the ability to mediate cytotoxicity against MHC class I-negative targets and

to produce IFN-γ. iNK acquire all these features during the transition to the next maturation stage after which they closely resemble CD56bright Everolimus research buy in peripheral blood and are considered to be mature. The proof of progression from CD56bright to CD56dim Reverse transcriptase has remained elusive for a long time. CD56bright isolated from peripheral blood start to express KIR and CD16, downregulate c-kit and acquire cytolytic activity upon activation by IL-2 or IL-15 5, 12. However, IL-15 induces only CD56dim-like

levels of CD56, CD16 and KIR in CD56bright in contact with fibroblasts 20 or after infusion of CD56bright into immune-deficient mice 20, 21. Furthermore, skewing NK-cell differentiation toward CD56dim is far superior when IL-15 is trans-presented by IL-15Rα-Fc 21, which mimics the way IL-15 is presented by dendritic cells to NK cells in lymph nodes 22. Although these results provide direct evidence that a transition of CD56bright to CD56dim may occur, it remains unclear to what extent this transition represents the typical differentiation pathway in vivo. Furthermore, the fact that CD56bright may acquire many features of CD56dim may not be ground enough to denote them as less mature or as CD56dim precursors, not only because they largely outnumber CD56dim5, 6 but also because most CD56bright probably exert their effector functions without ever “maturing” into CD56dim.

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