α1 / α2 domains of H-2Dd, but not H-2Ld, induce “missing self” reactivityin vivo – No effect of H-2Ld on protection against NK cells expressing the inhibitory receptor Ly49G2

Johansson, Maria H.; Höglund, Elin; Nakamura, Mary C.; Ryan, James C.

doi:10.1002/(sici)1521-4141(199812)28:12<4198::aid-immu4198>3.0.co;2-9

Cited by 25 publications

(6 citation statements)

References 39 publications

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“…Hanke et al have demonstrated that H-2D d tetramers stained NK cells expressing Ly49A + stronger than they stained Ly49G2 + NK cells, supporting the idea of differences in the strength of binding between H-2D d and these two receptors ( 20 ). It is not known how differences in Ly49 receptor affinity affect NK cell function, but our previous and present data suggest that difference in binding strength is associated with reduced amount, but not absence, of acquired MHC class I ligand after in vivo transfer (this study), and a small but reproducible receptor downregulation in the presence of H-2D d ( 28 ).…”

Section: Discussionmentioning

confidence: 49%

Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors

Sjöström

Eriksson

Cerboni

et al. 2001

The Journal of Experimental Medicine

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Murine natural killer (NK) cells express inhibitory Ly49 receptors specific for major histocompatibility complex (MHC) class I molecules. We report that during interactions with cells in the environment, NK cells acquired MHC class I ligands from surrounding cells in a Ly49-specific fashion and displayed them at the cell surface. Ligand acquisition sometimes reached 20% of the MHC class I expression on surrounding cells, involved transfer of the entire MHC class I protein to the NK cell, and was independent of whether or not the NK cell expressed the MHC class I ligand itself. We also present indirect evidence for spontaneous MHC class I acquisition in vivo, as well as describe an in vitro coculture system with transfected cells in which the same phenomenon occurred. Functional studies in the latter model showed that uptake of H-2Dd by Ly49A+ NK cells was accompanied by a partial inactivation of cytotoxic activity in the NK cell, as tested against H-2Dd-negative target cells. In addition, ligand acquisition did not abrogate the ability of Ly49A+ NK cells to receive inhibitory signals from external H-2Dd molecules. This study is the first to describe ligand acquisition by NK cells, which parallels recently described phenomena in T and B cells.

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Section: Discussionmentioning

confidence: 49%

Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors

Sjöström

Eriksson

Cerboni

et al. 2001

The Journal of Experimental Medicine

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“…Interestingly, it has been reported that a spontaneous murine mutant, BALB/ c-H-2dm2, expresses K d and D d but not L d antigens, due to a deletion of about 140 kb that includes the L d gene. 40 In this connection we have also observed the loss of HLA A and B locus-specific products together with the retention of HLA C expression in some human tumors. 34 Spontaneous murine mutant, BALB/c-H-2dm1 also has a mutation in this zone.…”

Section: Mhc Class I Expression Of Metastatic Colonies From Nude Micementioning

confidence: 56%

Immunoselection by T lymphocytes generates repeated MHC class I-deficient metastatic tumor variants

et al. 2000

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Alteration of MHC class I molecule expression is a widespread mechanism used by tumor cells to evade T cell responses. It has long been proposed that the origin of these MHC class I-negative or -deficient tumor variants is T cell immune selection. However, there are no experimental or clinical data to substantiate this hypothesis, and this issue is currently the subject of debate. Here we report that an H-2 class I-negative fibrosarcoma tumor clone generated MHC class I-negative spontaneous lung metastases in immunocompetent syngeneic BALB/c mice. Interestingly, the same B9 clone generated MHC class I-positive metastatic nodes, under basal conditions, in athymic nu/nu BALB/c mice. This phenomenon was observed in the metastatic nodules generated after a period of in vivo growth but not in the primary tumors growing locally in the footpad. These findings support the hypothesis that the H-2 phenotype of metastatic nodes is influenced by the T cell repertoire of the host, since in the absence of this T cell pressure (i.e., in nude mice) the metastatic nodes 'recovered' H-2 class I expression. In addition, 2 different phenotypes were found when the metastatic nodules obtained from immunocompetent mice were treated with IFN-␥. One phenotype, present in 83% of the colonies, was characterized by resistance of the L d molecule to IFN-␥ induction, due to a deletion involving the L d gene. The second phenotype (17% of the colonies) was similar to the original B9 clone and was characterized by the response of K, D and L class I genes to IFN-␥. These data provide evidence that the changes in MHC class I expression during tumor development might not be random but could be predictable.

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“…C57BL/6 (abbreviated B6, H-2K b D b ) and B6.Tap −/− mice were originally obtained from the Bomholt Gaard breeding and research center (Ry, Denmark). D8 mice (transgenic for H-2D d on B6 background) and L3 mice (transgenic for H-2L d on B6 background) have been previously described [15], [30]. B6.K b−/− , B6.D b−/− and B6.K b−/− D b−/− mice were generated as described [31], [32], [33].…”

Section: Methodsmentioning

confidence: 99%

“…Different MHC class I alleles educate NK cells in a quantitatively different manner, i.e. they have different educating impact on NK cells [15], [16]. We have recently shown that the self MHC class I alleles that are present in an individual dictate the magnitude of response of individual NK cells and control the quality of effector responses that each NK cell performs upon stimulation.…”

Section: Introductionmentioning

confidence: 99%

Natural Killer Cell Tolerance Persists Despite Significant Reduction of Self MHC Class I on Normal Target Cells in Mice

et al. 2010

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BackgroundA major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8+ T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known.Methodology/Principal FindingsIn this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further effect on the degree of Ly49 downmodulation. Furthermore, a single MHC class I allele could downmodulate up to three Ly49 receptors on individual NK cells. Only when NK cells simultaneously expressed several Ly49 receptors and hemizygous MHC class I levels, a putative threshold for Ly49 downmodulation was reached.ConclusionCollectively, our findings suggest that in interactions between NK cells and normal untransformed cells, MHC class I molecules are in most cases expressed in excess compared to what is functionally needed to ensure self tolerance and to induce maximal Ly49 downmodulation. We speculate that the reason for this is to maintain a safety margin for otherwise normal, autologous cells over a range of MHC class I expression levels, in order to ensure robustness in NK cell tolerance.

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α1 / α2 domains of H-2Dd, but not H-2Ld, induce “missing self” reactivityin vivo – No effect of H-2Ld on protection against NK cells expressing the inhibitory receptor Ly49G2

Cited by 25 publications

References 39 publications

Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors

Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors

Immunoselection by T lymphocytes generates repeated MHC class I-deficient metastatic tumor variants

Natural Killer Cell Tolerance Persists Despite Significant Reduction of Self MHC Class I on Normal Target Cells in Mice

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