Human Natural Killer cell maturation defect supports in vivo CD56bright to CD56dim lineage development

DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; URIARTE, IGNACIO; GIRART, MARÍA VICTORIA; SARDAÑONS, JESSICA; COMAS, DORINA ILEANA; DI GIOVANNI, DANIELA; GAILLARD, MARÍA INÉS; BEZRODNIK, LILIANA; ZWIRNER, NORBERTO WALTER

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 51677 - 51689

1932-6203

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-g 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.