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

Arnika Kathleen Wagner,Petter Höglund,Sadia Salam,Hanna Brauner,Rossana Tallerico,Maria Helena Johansson,Stina Linnea Wickström,Ennio Carbone,Tadepally Lakshmikanth,Klas Kärre

doi:10.1158/2326-6066.cir-15-0001

Arnika Kathleen Wagner, Petter Höglund + Show 8 more

Open Access

https://doi.org/10.1158/2326-6066.cir-15-0001

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Abstract

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 graft-versus-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 graft-versus-leukemia effects without causing graft-versus-host disease and may also be utilized to improve immunotherapy.

Highlights

Natural killer (NK) cells belong to the innate immune system and are important in responses to infections, cancer, and transplants
B6 mice treated with 5E6 F(ab0)2 against Ly49C/I showed reduced NK cell–mediated rejection of MHC class IÀ spleen cells
There was no effect when mice were treated with F(ab0)2 against the non–selfspecific inhibitory receptor Ly49G2, supporting an argument that the interference between self MHC class I and Ly49 receptors was required for reduced rejection of MHC class IÀ spleen cells. 5E6 F(ab0)2 treatment did not change the size or cellularity of the spleen (Supplementary Fig. S1)

Summary

Introduction

Natural killer (NK) cells belong to the innate immune system and are important in responses to infections, cancer, and transplants. They kill virus-infected or transformed cells and secrete cytokines that regulate other immune responses [1]. NK cell activation is mediated by germline encoded receptors that bind to ligands expressed by normal and malignant cells [2, 3]. Activation is balanced by inhibitory MHC class I–specific receptors: killer cell immunoglobulin-like receptors (KIR) in humans, Ly49 in mice, and NKG2A/CD94 receptors expressed in both species [2]. The presence of inhibitory MHC class I–specific receptors allows NK cells to react to "missing self," i.e., insufficient amounts of self MHC class I on target cells [4, 5].

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