Natural killer (NK)1 cells are large granular lymphocytes that provide a first innate immune defense. They are able to kill virus-infected and transformed cells and furthermore release cytokines and chemokines to activate adaptive immune cells (1, 2).The balance of signals from activating and inhibitory NK cell surface receptors tightly regulates NK cell activity. Activated NK cells release lytic granules through a process called degranulation. Therefore, NK cell cytotoxicity requires the formation of the F-actin-rich NK immune synapse (NKIS) and the transport of Perforin-containing lytic granules to the NKIS. Furthermore, this process requires granule-associated MYH9 protein (non-muscle Myosin IIa) mediating the interaction of granules with F-actin at the NKIS (3-5), leading to lytic granule exocytosis. Whereas related phenotypes and functional properties are well characterized, the underlying regulatory protein network mediating differentiation, cytokine release, and cytotoxicity, is still incomplete.NK cells are defined by the expression of the surface molecule CD56 (NCAM1) and the absence of the T cell receptor (TCR) associated protein CD3 and can be further subdivided into subsets (6, 7). CD56 expressing cells originate from CD34 ϩ HSCs. Notably, the commitment to the NK lineage includes discrete steps from HSC to cells, expressing high CD56 levels (CD56 bright ) (8, 9), which act immune regulatory by the release of various cytokines. NK cells with low CD56-expression (CD56 dim ) predominantly constitute cytotoxic responses (10, 11). Contact of CD56 (NCAM1) with fibroblasts (12) and neutrophils (13) supports the differentiation process from CD56 bright to CD56 dim NK cells. The progression of early differentiation steps is proven by telomere length investigation (14 ) and early presence in blood after HSC transplantation (HSCT) (14, 15). Indeed, CD56 dim NK cells are able to change their phenotypic properties, which can be correlated with continued differentiation throughout their whole lifespan (15-18). CD57 was determined to be a senescence marker in T cells (19 1 The abbreviations used are: NK, natural killer; CD56, NK cell marker; NCAM1, neural cell adhesion molecule; CD57, senescence marker in T and NK cells (HNK-1 or Leu-7); CMV, cytomegalovirus; CPDA-1, anticoagulant , containing citric acid, sodium citrate, monobasic sodium phosphate and dextrose; CTLs, cytotoxic T lymphocytes; FDR, false discovery rate; HLA, self-human leukocyte antigen; HSC, hematopoietic stem cell; iTRAQ, isobaric tags for relative and absolute quantification in mass spectrometry; KIR, killer immunoglobulin-related receptors in NK cells; LC-MS/MS, liquid-chromatography coupled with peptide sequencing (mass spectrometry); MAD, median absolute deviation from the median; NKIS, NK cell immune synapse; RF, regulation factor.
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