Altered expression of Ly49 inhibitory receptors on NK cells from MHC class I deficient mice

Salcedo, Margarita; Diehl, Alexander D.; Olsson-Alheim, Mats Y.; Sundbäck, Jonas; Kaer, Luc Van; Kärre, Klas

doi:10.1016/s0165-2478(97)86556-x

Cited by 55 publications

(81 citation statements)

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“…and express these at higher levels (29,38,39). NK cells from dnSHP-1 transgenic and me v mice also showed a tendency toward increased usage of certain inhibitory Ly49 receptors.…”

Section: Discussionmentioning

confidence: 99%

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Lowin-Kropf

Kunz

Beermann³

et al. 2000

The Journal of Immunology

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NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with β2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.

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“…and express these at higher levels (29,38,39). NK cells from dnSHP-1 transgenic and me v mice also showed a tendency toward increased usage of certain inhibitory Ly49 receptors.…”

Section: Discussionmentioning

confidence: 99%

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Lowin-Kropf

Kunz

Beermann³

et al. 2000

The Journal of Immunology

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“…In addition to cell surface levels, MHC-I expression contracts the size of NK cell subsets expressing MHC-I receptors [17][18][19]. We noted alterations in the usage of several Ly49 receptors in a number of different mouse strains (Table 2): e.g., Ly49A usage was expanded in lMT -/-mice and contracted in TCRbd -/-mice.…”

Section: Lymphocytes Influence the Repertoire Of Mhc-i Receptors On Nmentioning

confidence: 93%

“…The expression level of Ly49 family receptors is reduced in the presence of the respective MHC-I ligand in mice [17,18]. As compared to B6 mice, the absence of B cells (in lMT -/-and RAG-1 -/-mice) resulted in increased cell surface levels (115AE12% and 131AE18%, respectively, of B6) of the Ly49I receptor, which is specific for H-2K b , a self-MHC-I molecule in B6 mice.…”

Section: Lymphocytes Influence the Repertoire Of Mhc-i Receptors On Nmentioning

confidence: 99%

“…Additional factors such as IL-15 or LTa are also required to establish normal Ly49 receptor representation [15,16]. Subsequently, the usage of MHC-I receptors is modified by MHC I expression, which contracts receptor usage and overlap [17][18][19]. In addition, in the presence of MHC-I ligand the cell surface density of receptors is reduced [17].…”

Section: Introductionmentioning

confidence: 99%

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T and B lymphocytes exert distinct effects on the homeostasis of NK cells

2006

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There is growing evidence that lymphocytes impact the development and/or function of other lymphocyte populations. Based on such observations we have tested whether the NK cell compartment was phenotypically and functionally altered in the absence of B and/or T cells. Here we show that T cell deficiency significantly accelerates BM NK cell production and the subsequent seeding of splenic and liver NK cell compartments. In contrast, B cell deficiency reduces splenic NK cell survival. In the absence of T and B cells, the size of the NK cell compartments is determined by the combination of these positive and negative effects. Even though NK cell homeostasis is significantly altered, NK cells from T and/or B cell-deficient mice show a normal capacity to kill a susceptible target cell line and to produce IFN. Nevertheless, we noted that the usage of MHC class Ispecific Ly49 family receptors was significantly altered in the absence of T and/or B cells. In general, B cell deficiency expanded Ly49 receptor usage, while T cell deficiency exerted both positive and negative effects. These findings show that B and T cells significantly and differentially influence the homeostasis and the phenotype of NK cells.

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“…Specifically, it has been suggested that MHC class I expression decreases the frequency of cells expressing several self-specific receptors (14,(19)(20)(21), whereas cells expressing only one such receptor were increased in frequency (21,22). Such repertoire effects have been interpreted as a means of limiting the frequency of NK cells that would be inhibited too easily and at the same time enriching for the most useful NK cells (i.e., those expressing single Ly49 receptors).…”

mentioning

confidence: 99%

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Brodin

Lakshmikanth

Kärre

et al. 2012

The Journal of Immunology

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A major task for the immune system is to secure powerful immune reactions while preserving self-tolerance. This process is particularly challenging for NK cells, for which tolerizing inhibitory receptors for self-MHC class I is both cross-reactive and expressed in an overlapping fashion between NK cells. We show in this study that during an education process, self-MHC class I molecules enrich for potentially useful and contract potentially dangerous NK cell subsets. These processes were quantitatively controlled by the expression level of the educating MHC class I allele, correlated with susceptibility to IL-15 and sensitivity to apoptosis in relevant NK cell subsets, and were linked to their functional education. Controlling the size of NK cell subsets with unique compositions of inhibitory receptors may represent one mechanism by which self-MHC class I molecules generate a population of tolerant NK cells optimally suited for efficient missing self-recognition.

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Altered expression of Ly49 inhibitory receptors on NK cells from MHC class I deficient mice

Cited by 55 publications

References 0 publications

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

T and B lymphocytes exert distinct effects on the homeostasis of NK cells

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

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