CD56bright Natural Killer Cells
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P219
2025-12-10
27
CD56bright NK cells appear to play an immunoregulatory role in the innate immune response. CD56bright NK produce multiple cytokines and chemokines, have a relatively high proliferative capacity, reside primarily in the parafollicular T cell–rich region of secondary lymphoid tissue (SLT), and have modest levels of cytolytic granules, low expression of KIR and FcγRIII. CD56bright NK cells are unique among cytotoxic effector cells in their constitutive expression of the heterotrimeric high-affinity IL-2 Rαβγ complex, making them responsive to picomolar concentrations of IL-2 released by activated T cells in the SLT parafollicular region. As noted, CD56bright NK cells comprise only about 10% of the circulating NK population but predominate almost to the exclusion of the CD56dim NK subset in SLT. This distribution likely results from their selective expression of a number of receptors that assist in homing cells to SLT and retaining them there (e.g., CCR7 and CD62L). NK cell precursor expression of the C-type lectin-like surface activating receptor NKp80 correlates with NK cell functional maturity in SLTs. NKp80 may play an important regulatory role during NK maturation in SLTs related to the acquisition of cytotoxic functions and/or cytokine-production.
Chemokine receptor repertoires (and thus migration patterns) are differentially aligned among NK cell sub-populations. Compared to CD56dim NK cells, CD56bright NK cells express higher levels of chemokine (C-X-C motif) receptor 4 (CXCR4) which is the receptor for CXCL12 (also knowns as SDF-1α/β). CXCL12/SDF-1 stimulates NK cell migration and its production by trophoblasts is responsible for maintaining a population of CD56bright NK cells within the decidua of the uterus during pregnancy. The CD 56bright subset is directed to lymph nodes via their expression of CCR7, and they preferentially express CXCR3 which binds the interferon-inducible chemokines CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC). This pattern of chemokine receptor expression, along with the high levels of the adhesion molecule L-Selectin (CD62L), helps to explain the prevalence of CD56bright NK cells in secondary lymphoid tissues. In contrast, CD56dim NK cells uniquely express high levels of receptors specific for inflammatory chemokines such as CXCR1, CXCR2, and CX3CR1. CXCR1 binds IL-8 (CXCL8), the levels of which are increased in the setting of acute viral infections and correlate with disease severity. Fractalkine (CX3CL1), the ligand for CX3CR1, is induced at sites of inflammation and acts as an adhesion protein for cells with CX3CR1 expression, resulting in retention of NK cells on vessel walls. As a member of the seven transmembrane domain G protein-coupled receptor family, CX3CR1 activation leads to NK cell stimulation via calcium mobilization and the initiation of mitogen activated protein kinase (MAPK) and PI3 kinase signaling. Thus, expression of these chemokine receptors allows NK cells to traffic to local areas of inflammatory response to augment and modify the host immune response. Altered expression of chemokine ligand/receptor pairs can also promote malignant disease. In murine models of multiple myeloma, there is increased bone marrow expression of CXCL9 and CXCL10 which leads to downregulation of CXCR3 on NK cells and reduced migration and retention of NK cells to this site.
Not unexpectedly, NK cell expression of adhesion molecules also differs between the two CD56 subsets. An analysis of CD56dim NK cells reveals that they express CD11a at a high level as compared to the bright subset. CD11a is the α chain of the αγL β2 integrin (also known as leukocyte function associated antigen 1 [LFA-1]. Integrins bind to a wide variety of ligands in the extracellular matrix, on the surface of other cells and also soluble proteins. In contrast, CD56bright NK cells exhibit high-level expression of CD11c. They also express high levels of CD2, CD44, CD49e, CD54, and CD62L as compared to the dim subset. CD44 binds to hyaluronic acid in the extracellular matrix. CD49e belongs to the integrin alpha chain family and associates with CD29 (integrin beta1) to form the VLA-5 receptor which binds to fibronectin and fibrinogen. CD54 is upregulated during activation and strengthens the NK-target during the lytic process. L-selectin (CD62L) is a type-I transmembrane glycoprotein that has been identified as a tethering/rolling receptor. As a result of these differing repertoires of adhesion molecules and chemokine receptors, the migratory properties of NK cells diverge quite significantly. The CD56bright subset migrates preferentially to secondary lymphoid organs whereas CD56dim NK cells are attracted to sites of acute inflammation.
The ability of CD56bright NK cells to produce an abundant variety of cytokines and chemokines compared with the CD56dim subset likely relates more to the differential expression of both negative and positive regulators of cytokine/chemokine production and less to constitutive expression of cytokine-activating receptors. For example, CD56bright NK cells have little or no expression of two negative regulators of cytokine/chemokine production, namely SHIP-1 (Src homology 2 domain containing inositol 5-phosphatase 1) and HLX (H2.0-like homeobox 1). CD56dim NK cells lack constitutive expression of a positive regulator of cytokines called SET. Single-cell transcriptomic analyses generally support the use of CD56 as a means of identifying NK cell subsets with mature populations expressing high levels of CXCR1, TIM-3 (inhibitory checkpoint molecule), and ZEB2.
الاكثر قراءة في المناعة
اخر الاخبار
اخبار العتبة العباسية المقدسة
