Clonal Acquisition of Inhibitory Ly49 Receptors on Developing NK Cells Is Successively Restricted and Regulated by Stromal Class I MHC

Roth, Claude; Carlyle, James R.; Takizawa, Hisao; Raulet, David H.

doi:10.1016/s1074-7613(00)00015-7

Cited by 119 publications

(114 citation statements)

References 31 publications

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“…In bone marrow, it has been reported that CD146 1 subendothelial stromal cells are responsible for the ectopic reconstitution of a hematopoietic microenvironment [16]. It is known that bone marrow stromal cells do play a role in NK cell maturation [31] and we found CD146 expression in some NK cells from mouse bone marrow. Thus, if CD146 homophilic interactions occur in vivo, the adhesive properties of CD146 could influence NK cell maturation.…”

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confidence: 48%

Mouse CD146/MCAM is a marker of natural killer cell maturation

et al. 2008

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CD146/melanoma cell adhesion molecule is an adhesion molecule expressed by endothelial cells and by a small fraction of activated T and B lymphocytes in humans. In order to analyze the pattern of CD146 expression in mouse leukocytes at steady-state conditions, we generated a set of novel rat anti-mouse CD146 monoclonal antibodies. CD146 expression was undetectable on monocytes, dendritic cells, T cells or B cells, but was expressed on about 30% of neutrophils and 60% of NK cells. Within murine lymphocytes, CD146 was defined as a novel NK-specific surface molecule. An increased percentage of CD146 1 cells was found in the most mature CD27 À CD11b 1 NK cell subpopulation, which also displays higher expression of Ly49C/I, Ly49D and KLRG1 and lower expression of NKG2A/C/E molecules. CD146 1 NK cells were found to be less cytotoxic and produce less IFN-c than CD146 À NK cells upon stimulation with target cells or activating antibodies. These findings define CD146 as a marker of mouse NK cell maturation that may be used as an alternative to the combined use of CD27 and CD11b staining to detect final stages of NK cell maturation.Key words: Adhesion . Antibodies . CD146/MCAM . Maturation . NK cells Introduction CD146, also known as melanoma cell adhesion molecule (MCAM or Mel-CAM), MUC18, S-Endo1, A32 antigen, is an integral membrane glycoprotein of 113 kDa that belongs to the Ig superfamily with a characteristic V-V-C2-C2-C2 domain structure [1]. Two others members of this family have been identified in humans: basal-cell adhesion molecule and activated leukocytecell adhesion molecule, also called CD166 [2,3]. Basal-cell adhesion molecule is a splice variant of the Lutheran blood group glycoprotein that is reported to bind laminin [3]. Activated leukocyte-cell adhesion molecule is a costimulatory molecule mediating homophilic interaction and heterophilic interaction with CD6 and is involved in activation and trafficking of leukocytes into the central nervous system [4]. CD146 was originally defined as a marker of tumor progression and metastasis formation in human melanoma [5]. Overexpression of CD146 in CD146-negative melanoma cells renders these cells highly metastatic after injection in immunodeficient mice [6]. Moreover, injection of a humanized anti-CD146 mAb in immunodeficient mice bearing human melanomas significantly reduces the tumor size and the number of metastases [7]. The adhesive functions of CD146 were demonstrated using a solid-phase adhesion test in which both CD146-positive and CD146-negative melanoma cells bound to eucaryotic recombinant CD146 protein, suggesting that CD146 can mediate both homophilic and heterophilic interaction with an as yet unidentified ligand [8,9]. Using S-Endo1 mAb, we previously detected cell surface expression of CD146 on human vascular endothelial cells, whatever vessel caliber or anatomical region [10]. On cultured endothelial cells, CD146 is mainly located at the intercellular junctions and is involved in inter-endothelial cell adhesion and paracellular permeability [11,1...

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confidence: 48%

Mouse CD146/MCAM is a marker of natural killer cell maturation

et al. 2008

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“…Data presented to date are consistent with both of these models. Recent data from two in vitro cell culture systems suggest that NK cells begin to express different Ly49 receptors at different times during their development, although the order of receptor expression differed between the two systems (49,50). The sequential and selection models make different predictions about how expression of a single Ly49 receptor on all NK cells would alter the repertoire development.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro data suggest that there may be a time element that needs to be considered (49,50). During NK cell differentiation, there may be a discrete stage in which Ly49 receptor genes can be activated.…”

Section: Discussionmentioning

confidence: 99%

MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells

Fahlén

Lendahl

Sentman

2001

The Journal of Immunology

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This study aims to determine how the interaction of Ly49 receptors with MHC class I molecules shapes the development of the Ly49 repertoire. We have examined the percentage of NK cells that expressed Ly49A, Ly49G2, and Ly49D in single and double Ly49A/C-transgenic mice on four different MHC backgrounds, H-2b, H-2d, H-2b/d, and β2-microglobulin−/−. The results show that the total numbers of NK cells were not different among the strains. The prior expression of a Ly49 receptor capable of binding to self MHC class I altered the percentage of NK cells expressing endogenous Ly49A, Ly49G2, and Ly49D even in mice in which no MHC ligand was present for the latter receptors. The NK cells in the Ly49-transgenic mice expressed the same level of endogenous Ly49 receptors as wild-type mice of a similar MHC background. In contrast, the number of NK T cells was reduced in mice in which the Ly49 transgene could bind to a MHC class I molecule. The onset of Ly49 receptor expression on NK cells during ontogeny was not altered in the presence of transgenic Ly49 receptors. These data support a sequential model and argue against a selection model for Ly49 repertoire development on NK cells.

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“…An orderly acquisition of NKR has been described on Leukemia mouse NK cells. [41][42] It is thus possible that shaping of the NKR repertoire is also sequential in humans, with CD158a/h being expressed later in the course of NK cell maturation. Nevertheless, the present phenotypic characterization supports the fact that NK cells present in hematopoietic grafts, and thus infused in patients during the course of allogeneic transplantation, are equipped with multiple NKR, and are therefore capable of interactions with MHC class I molecules.…”

Section: Figurementioning

confidence: 99%

Analysis of donor NK and T cells infused in patients undergoing MHC-matched allogeneic hematopoietic transplantation

et al. 2002

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We retrospectively analyzed the percentages and absolute numbers of T cells, natural killer (NK) cells and NK cell subsets in cryopreserved samples of either bone marrow or blood non-T cell-depleted allogeneic MHC-matched hematopoietic grafts. Using flow cytometry, we found higher numbers of NK cells in aphereses than in bone marrow collections. We further investigated the distribution of NK cell subsets, defined by the cell surface expression of MHC class I-specific receptors, in these allogeneic grafts. The distribution of NK cell subsets from the two different origins were similar, with the exception of the CD158a/h + NK cell subset, whose size appeared to be smaller in bone marrow. The search for relations between the numbers of infused cells and post-transplantation events demonstrated that increasing numbers of infused T cells but not NK cells are related with decreased overall survival. Our study highlights the toxicity of infused T cells but not NK cells in allogeneic MHC-matched hematopoietic grafts. These data pave the way for further trials to investigate the effect of NK cell infusion in MHC-matched allogeneic transplantation, and in particular whether ex vivo NK cell expansion and activation may enhance the anti-tumoral effect of the procedure and decrease its morbidity.

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Clonal Acquisition of Inhibitory Ly49 Receptors on Developing NK Cells Is Successively Restricted and Regulated by Stromal Class I MHC

Cited by 119 publications

References 31 publications

Mouse CD146/MCAM is a marker of natural killer cell maturation

Mouse CD146/MCAM is a marker of natural killer cell maturation

MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells

Analysis of donor NK and T cells infused in patients undergoing MHC-matched allogeneic hematopoietic transplantation

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