Adaptations of Natural Killer Cells to Self-MHC Class I

Bessoles, Stéphanie; Grandclement, Camille; Alari-Pahissa, Elisenda; Gehrig, Jasmine; Jeevan-Raj, Beena; Held, Werner

doi:10.3389/fimmu.2014.00349

Cited by 30 publications

(30 citation statements)

References 47 publications

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“…This is the simplest, but not the only model to explain our data. For example, adaptation of mature NK cells could be determined by a different mechanism than that responsible for the original education (44). This can be tested only when the molecular mechanisms involved in education are clarified.…”

Section: Discussionmentioning

confidence: 99%

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Wagner

Wickström

Tallerico

et al. 2016

Cancer Immunology Research

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Natural killer (NK) cells are most efficient if their targets do not express self MHC class I, because NK cells carry inhibitory receptors that interfere with activating their cytotoxic pathway. Clinicians have taken advantage of this by adoptively transferring haploidentical NK cells into patients to mediate an effective graftversus-leukemia response. With a similar rationale, antibody blockade of MHC class I-specific inhibitory NK cell receptors is currently being tested in clinical trials. Both approaches are challenged by the emerging concept that NK cells may constantly adapt or "tune" their responsiveness according to the amount of self MHC class I that they sense on surrounding cells. Hence, these therapeutic attempts would initially result in increased killing of tumor cells, but a parallel adaptation process might ultimately lead to impaired antitumor efficacy. We have investigated this question in two mouse models: inhibitory receptor blockade in vivo and adoptive transfer to MHC class I-disparate hosts. We show that changed self-perception via inhibitory receptors in mature NK cells reprograms the reactivity such that tolerance to healthy cells is always preserved. However, reactivity against cancer cells lacking critical MHC class I molecules (missing self-reactivity) still remains or may even be increased. This dissociation between activity against healthy cells and tumor cells may provide an answer as to why NK cells mediate graftversus-leukemia effects without causing graft-versus-host disease and may also be utilized to improve immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Wagner

Wickström

Tallerico

et al. 2016

Cancer Immunology Research

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“…MHC downregulation, referred to as ‘missing-self’ hypothesis, is one of the prominent strategies used by tumor cells, particularly of hematologic origin, to escape from adaptive cell-mediated immunity. In such a situation, NK cells are capable of sensing the absence of MHC-I and efficiently eliminate transformed cells [32, 33]. However, various kinds of tumor cells display different adaptation mechanisms to bypass the immune surveillance function of NK cells [34].…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

et al. 2019

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Background: In this study, the expression pattern of NKp30 and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3), as candidates for activating and inhibitory receptors of NK cells, were evaluated in patients with chronic lymphocytic leukemia (CLL). Patients and Methods: 24 CLL patients and 19 healthy controls were enrolled. Fresh peripheral blood was collected from all subjects and stained with fluorochrome-conjugated antibodies. The frequency of CD56+/CD3–/NKp30+ and CD56+/CD3–/Tim-3+ cells was determined by multicolor flow cytometry. Results: Our results revealed that Tim-3 is significantly upregulated on natural killer (NK) cells of CLL patients in comparison to healthy controls. NK cells of CLL patients showed lower expression of NKp30-activating receptor compared to controls. Tim-3 expression pattern on NK cells of CLL patients was correlated with poor prognostic factors including low hemoglobin level, high absolute lymphocyte count, and high serum C-reactive protein level. Conclusion: Dysregulated expression of Tim-3 and NKp30 receptors confirms the exhaustion state of NK cells in CLL. Our data introduce Tim-3 as a promising biomarker and potential target for immunotherapy of CLL.

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“…11 Overall, NK cell education is a plastic process that adapts to environmental changes, and this adaptation may explain the existence of responsive NK cell subsets lacking inhibitory receptors specific for self MHC-I molecules. 82 …”

Section: Reversal Of Nk Cell Education In Tumor and Virus Infectionmentioning

confidence: 99%

NK cell education via nonclassical MHC and non-MHC ligands

2016

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Natural killer (NK) cell education, a process for achieving functional maturation and self-tolerance, has been previously defined by the interaction between self-major histocompatibility complex class I (MHC-I) molecules and their specific inhibitory receptors. Over the past several years, growing evidence has highlighted the important roles of nonclassical MHC-I and non-MHC-I molecules in NK cell education. Herein, we review the current knowledge of NK cell education, with a particular focus on nonclassical MHC-I- and non-MHC-I-dependent education, and compare them with the classical MHC-I-dependent education theory. In addition, we update and extend this theory by presenting the 'Confining Model', discussing cis and trans characteristics, reassessing quantity and quality control, and elucidating the redundancy of NK cell education in tumor and virus infection.

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Adaptations of Natural Killer Cells to Self-MHC Class I

Cited by 30 publications

References 47 publications

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

NK cell education via nonclassical MHC and non-MHC ligands

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