MHC-I Molecules Selectively Inhibit Cell-Mediated Cytotoxicity Triggered by ITAM-Coupled Activating Receptors and 2B4

Rubén Corral-San Miguel,Trinidad Hernández-Caselles,Pilar García-Peñarrubia,María Martínez-Esparza,Antonio José Ruiz Alcaraz,Jacques Zimmer

doi:10.1371/journal.pone.0107054

Rubén Corral-San Miguel, Trinidad Hernández-Caselles + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0107054

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Abstract

NK cell effector functions are controlled by a combination of inhibitory receptors, which modulate NK cell activation initiated by stimulatory receptors. Most of the canonical NK cell inhibitory receptors recognize allelic forms of classical and non-classical MHC class I molecules. Furthermore, high expression of MHC-I molecules on effector immune cells is also associated with reverse signaling, giving rise to several immune-regulatory functions. Consequently, the inhibitory function of MHC class I expressed on a human NKL cell line and activated primary NK and T cells on different activating receptors are analyzed in this paper. Our results reveal that MHC-I molecules display specific patterns of “selective” inhibition over cytotoxicity and cytokine production induced by ITAM-dependent receptors and 2B4, but not on NKG2D. This contrasts with the best known “canonical” inhibitory receptors, which constitutively inhibit both functions, regardless of the activating receptor involved. Our results support the existence of a new fine-tuner inhibitory function for MHC-I molecules expressed on cytotoxic effector cells that could be involved in establishing self-tolerance in mature activated NK cells, and could also be important in tumor and infected cell recognition.

Highlights

The mechanisms that control the activity of NK and other cytotoxic effector cells are determined by a fine balance between signals triggered by activating and inhibitory receptors, which determine the activation of the effector cell [1,2]
Taking advantage of the fact that two different receptors may be co-ligated on the membrane of effector cells, NKL cells were triggered with optimal concentrations of mAb against CD16, NKp46 (CD335), NKG2D (CD314) or 2B4 (CD244) Killer Activating Receptors (KARs), together with one of the following: isotype control Ab, anti-MHCI (W6/32) or mAb specific for the canonical inhibitory receptors ILT2 or CD94/NKG2A
The present results further reinforce and extend experimental evidence from our laboratory concerning the inhibitory function triggered by MHC-I molecules expressed on NKL, human primary NK cells and a CD8+ab T cell clone, K14B06 [10,11,12]

Summary

Introduction

The mechanisms that control the activity of NK and other cytotoxic effector cells are determined by a fine balance between signals triggered by activating and inhibitory receptors, which determine the activation of the effector cell [1,2]. Several NK cell-activating receptors may directly recognize ligands expressed on the surface of infected or stressed tumor target cells [1,2]. The best studied human (canonical) NK cell inhibitory receptors, Killer Ig-like receptors, (KIRs), Leukocyte Ig-like receptors (LILRs) and lectins-like receptors such as CD94/NKG2A, mediate self-tolerance through chronic cognate interaction with their ligands, mainly MHC (Major Histocompatibility Complex) class I molecules expressed on target cells. Loss of MHC-I expression by virus-infected or tumor cells leads to NK cell activation as proposed by the ‘‘missing-self hypothesis’’ [1,2,3]. It seems that the MHC-I environment redesigns NK cell receptor expression and reactivity [4]. MHC-I-deficient mice display reduced responsiveness despite having self–tolerant NK cells [6]

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