Cytotoxicity of CD56bright NK Cells towards Autologous Activated CD4+ T Cells Is Mediated through NKG2D, LFA-1 and TRAIL and Dampened via CD94/NKG2A

Natasja Nielsen,Pieter Spee,Lewis L Lanier,Birgitte Ursø,Niels Ødum,Johan K Sandberg

doi:10.1371/journal.pone.0031959

Abstract

In mouse models of chronic inflammatory diseases, Natural Killer (NK) cells can play an immunoregulatory role by eliminating chronically activated leukocytes. Indirect evidence suggests that NK cells may also be immunoregulatory in humans. Two subsets of human NK cells can be phenotypically distinguished as CD16+CD56dim and CD16dim/−CD56bright. An expansion in the CD56bright NK cell subset has been associated with clinical responses to therapy in various autoimmune diseases, suggesting an immunoregulatory role for this subset in vivo. Here we compared the regulation of activated human CD4+ T cells by CD56dim and CD56bright autologous NK cells in vitro. Both subsets efficiently killed activated, but not resting, CD4+ T cells. The activating receptor NKG2D, as well as the integrin LFA-1 and the TRAIL pathway, played important roles in this process. Degranulation by NK cells towards activated CD4+ T cells was enhanced by IL-2, IL-15, IL-12+IL-18 and IFN-α. Interestingly, IL-7 and IL-21 stimulated degranulation by CD56bright NK cells but not by CD56dim NK cells. NK cell killing of activated CD4+ T cells was suppressed by HLA-E on CD4+ T cells, as blocking the interaction between HLA-E and the inhibitory CD94/NKG2A NK cell receptor enhanced NK cell degranulation. This study provides new insight into CD56dim and CD56bright NK cell-mediated elimination of activated autologous CD4+ T cells, which potentially may provide an opportunity for therapeutic treatment of chronic inflammation.

Highlights

Natural killer (NK) cells are a critical component of the innate immune response, and were initially described as lymphoid cells that exhibit a ‘‘natural cytotoxicity’’ against virally infected cells and tumor cells without prior activation [1,2]
It is becoming increasingly appreciated that NK cells may play an immunoregulatory role in limiting autoimmune responses
Elimination of chronically activated immune cells is one mechanism by which NK cells perform this immunoregulatory role, and in this study we have demonstrated that activated NK cells degranulate and kill activated, but not resting, autologous CD4+ T cells

Summary

Introduction

Natural killer (NK) cells are a critical component of the innate immune response, and were initially described as lymphoid cells that exhibit a ‘‘natural cytotoxicity’’ against virally infected cells and tumor cells without prior activation [1,2]. Inhibitory receptors such as the inhibitory killer cell immunoglobulin-like receptors (iKIR) and the CD94/NKG2A heterodimer, monitor the absence of MHC class I proteins, which are normally expressed on healthy cells but can be downregulated upon infection or cellular stress. This ability to detect downregulation of MHC class I molecules is referred to as ‘‘missing-self’’ detection [4]. Blocking with an anti-NKG2A F(ab)’ fragment lead to enhanced lysis of Tfh and Th17 cells by NK cells, and disease arrest [7] These studies suggest that NK cells can regulate established immune responses both locally, at inflammatory sites, as well as systemically, in lymphoid organs

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