Effects of MHC Class I Alleles on Licensing of Ly49A+ NK Cells

Jonsson, Helena; Yang, Liping; Kim, Sung Jin; Taffner, Samantha M.; Yokoyama, Wayne M.

doi:10.4049/jimmunol.0904057

Cited by 59 publications

(81 citation statements)

References 49 publications

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“…It is possible that the lack of licensing of Ly49G 129 seen previously is due to H-2D b being a weak self-educator as shown in splenocyte rejection assays using H-2K b2/2 , H-2D b2/2 , or H-2K b2/2 H-2D b2/2 mice as donors (14,29). Furthermore, this hypothesis agrees with the observations that Ly49A can bind to H-2D b when the L chain is of mouse origin (24), but that Ly49A + NK cell subsets in H-2 b background mice produce little if any IFN-g upon stimulation, compared with Ly49A + subsets in H-2 d background mice (30); H-2D d is a strong ligand for Ly49A (31).…”

Section: Discussionsupporting

confidence: 79%

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

McFall

Al-Khattabi

et al. 2013

The Journal of Immunology

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Murine Ly49 receptors, which are expressed mainly on NK and NKT cells, interact with MHC class I (MHC-I) molecules with varying specificity. Differing reports of Ly49/MHC binding affinities may be affected by multiple factors, including cis versus trans competition and species origin of the MHC-I L chain (β2-microglobulin). To determine the contribution of each of these factors, Ly49G, Ly49I, Ly49O, Ly49V, and Ly49Q receptors from the 129 mouse strain were expressed individually on human 293T cells or the mouse cell lines MHC-I–deficient C1498, H-2b–expressing MC57G, and H-2k–expressing L929. The capacity to bind to H-2Db– and H-2Kb–soluble MHC-I tetramers containing either human or murine β2-microglobulin L chains was tested for all five Ly49 receptors in all four cell lines. We found that most of these five inhibitory Ly49 receptors show binding for one or both self–MHC-I molecules in soluble tetramer binding assays when three conditions are fulfilled: 1) lack of competing cis interactions, 2) tetramer L chain is of mouse origin, and 3) Ly49 is expressed in mouse and not human cell lines. Furthermore, Ly49Q, the single known MHC-I receptor on plasmacytoid dendritic cells, was shown to bind H-2Db in addition to H-2Kb when the above conditions were met, suggesting that Ly49Q functions as a pan–MHC-Ia receptor on plasmacytoid dendritic cells. In this study, we have optimized the parameters for soluble tetramer binding analyses to enhance future Ly49 ligand identification and to better evaluate specific contributions by different Ly49/MHC-I pairs to NK cell education and function.

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Section: Discussionsupporting

confidence: 79%

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

McFall

Al-Khattabi

et al. 2013

The Journal of Immunology

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“…A recent study in which the responsiveness of NK cells in mice with hemi-or homozygous expression of D d , similar to our mice, presented a different conclusion, although a trend toward stronger IFN-g responses in Ly49A + cells was described in homozygous mice (38). There could be several reasons for the discrepant results, including age and housing conditions of the mice, the stimulus used (antiNKp46 versus anti-NK1.1), and the type of statistical test applied.…”

Section: Discussionmentioning

confidence: 65%

“…More specific differences in the experimental outset may also play a role. For example, for Ly49 subset identification, Jonsson et al (38) included Abs to Ly49C/I/F/G2 and NKG2A in one dump channel to exclude NK cells expressing any of these receptors. In our experience, this method is less reliable as a strategy to separate NK cell subsets than unique fluorescent markings of each individual receptor in a multicolor setting.…”

Section: Discussionmentioning

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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“…Emerging evidence indicate that effector inhibition is not only the recruitment of a tyrosine phosphatase but also the recruitment of a macromolecular complex that potentially could give rise to different outcomes depending on the context (34). Indeed, other studies suggest that signal strength through a given receptor could modulate the ability of an NK-cell receptor to give rise to the licensing effect and that signal strength required for the licensing effect is different from that required to produce inhibition (35). Therefore it is possible that Ly49A receptors with mutant stalks could alter the ability of the receptor to deliver the appropriate signal strength necessary for licensing to occur.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cell licensing in mice with inducible expression of MHC class I

Ebihara

Jonsson

Yokoyama

2013

Proc. Natl. Acad. Sci. U.S.A.

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Mouse natural killer (NK) cells acquire effector function by an education process termed "licensing" mediated by inhibitory Ly49 receptors which recognize self-MHC class I. Ly49 receptors can bind to MHC class I on targets (in trans) and also to MHC class I on the NK-cell surface (in cis). Which of these interactions regulates NKcell licensing is not yet clear. Moreover, there are no clear phenotypic differences between licensed and unlicensed NK cells, perhaps because of the previously limited ability to study NK cells with synchronized licensing. Here, we produced MHC class I-deficient mice with inducible MHC class I consisting of a single-chain trimer (SCT), ovalbumin peptide-β2 microgloblin-H2K b (SCT-K b ). Only NK cells with a Ly49 receptor with specificity for SCT-K b were licensed after MHC class I induction. NK cells were localized consistently in red pulp of the spleen during induced NK-cell licensing, and there were no differences in maturation or activation markers on recently licensed NK cells. Although MHC class I-deficient NK cells were licensed in hosts following SCT-K b induction, NK cells were not licensed after induced SCT-K b expression on NK cells themselves in MHC class I-deficient hosts. Furthermore, hematopoietic cells with induced SCT-K b licensed NK cells more efficiently than stromal cells. These data indicate that trans interaction with MHC class I on hematopoietic cells regulates NK-cell licensing, which is not associated with other obvious phenotypic changes.tolerance | immunity | lymphocytes

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Effects of MHC Class I Alleles on Licensing of Ly49A+ NK Cells

Abstract: Material

Cited by 59 publications

References 49 publications

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

Optimized Tetramer Analysis Reveals Ly49 Promiscuity for MHC Ligands

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

Natural killer cell licensing in mice with inducible expression of MHC class I

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