Human Natural Killer Cell Maturation Defect Supports In Vivo CD56bright to CD56dim Lineage Development

Abstract

Two populations of human natural killer (NK) cells can be identified in peripheral blood. The majority are CD3−CD56dim cells while the minority exhibits a CD3−CD56bright phenotype. In vitro evidence indicates that CD56bright cells are precursors of CD56dim cells, but in vivo evidence is lacking. Here, we studied NK cells from a patient that suffered from a melanoma and opportunistic fungal infection during childhood. The patient exhibited a stable phenotype characterized by a reduction in the frequency of peripheral blood CD3−CD56dim NK cells, accompanied by an overt increase in the frequency and absolute number of CD3−CD56bright cells. These NK cells exhibited similar expression of perforin, CD57 and CD158, the major activating receptors CD16, NKp46, NKG2D, DNAM-1, and 2B4, as well as the inhibitory receptor CD94/NKG2A, on both CD56bright and CD56dim NK cells as healthy controls. Also, both NK cell subpopulations produced IFN-γ upon stimulation with cytokines, and CD3−CD56dim NK cells degranulated in response to cytokines or K562 cells. However, upon stimulation with cytokines, a substantial fraction of CD56dim cells failed to up-regulate CD57 and CD158, showed a reduction in the percentage of CD16+ cells, and CD56bright cells did not down-regulate CD62L, suggesting that CD56dim cells could not acquire a terminally differentiated phenotype and that CD56bright cells exhibit a maturation defect that might result in a potential altered migration pattern. These observations, support the notion that NK cells of this patient display a maturation/activation defect that precludes the generation of mature NK cells at a normal rate accompanied by CD56dim NK cells that cannot completely acquire a terminally differentiated phenotype. Thus, our results provide evidence that support the concept that in vivo CD56bright NK cells differentiate into CD56dim NK cells, and contribute to further understand human NK cell ontogeny.

NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment

“…In the peripheral blood, human NK cells are mostly CD3 ¡ CD56 dim cells with high cytotoxic activity, while CD3 ¡ CD56 bright cells excel in cytokine production 28 . In vitro evidence indicates that CD56 bright NK cells are precursors of CD56 dim NK cells and this might also be the case in vivo 29 . In addition, combined analysis of CD56 and CD16 expression during NK cell development indicates that their profiles changes as follows: CD56 bright CD16 ¡ !…”

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

“…Expression of cell surface receptors on NK cells was analyzed by FC as previ-ously described (75) and results were expressed as mean fluorescence intensity (MFI).…”

Natural killer cell deficiency

“…A separate recently reported spontaneous patient with pediatric melanoma and opportunistic fungal infection was also found to have an abnormal transition from CD56 bright to CD56 dim NK cells. 45 It is presently unclear as to whether the molecular pathways affected in these cohorts will functionally overlap with that of CNKD2. That said, neither of the two family cohorts have been defined to have MCM4 mutations (despite this having been evaluated – unpublished results) and thus it is likely that the CNKD category will encompass additional genetic mechanisms that impact the CD56 bright to CD56 dim NK cell transition.…”