Induction of Lectin-like Transcript 1 (LLT1) Protein Cell Surface Expression by Pathogens and Interferon-γ Contributes to Modulate Immune Responses

Claire Germain,Anders Meier,Teis Jensen,Perrine Knapnougel,Gwenola Poupon,Anne Lazzari,Anne Neisig,Katarina Håkansson,Tao Dong,Nicolai Wagtmann,Elizabeth D Galsgaard,Pieter Spee,Veronique M Braud

doi:10.1074/jbc.m111.285312

Abstract

CD161 is a C-type lectin-like receptor expressed on human natural killer (NK) cells and subsets of T cells. CD161 has been described as an inhibitory receptor that regulates NK cell-mediated cytotoxicity and IFN-γ production. Its role on T cells has remained unclear. Studies have shown that triggering of CD161 enhances NK T cell proliferation and T cell-IFN-γ production while inhibiting TNF-α production by CD8(+) T cells. Lectin-like transcript 1 (LLT1), the ligand of CD161, was found to be expressed on Toll-like receptor (TLR)-activated plasmacytoid and monocyte-derived dendritic cells (DC) and on activated B cells. Using newly developed anti-LLT1 mAbs, we show that LLT1 is not expressed on the surface of circulating B and T lymphocytes, NK cells, monocytes, and dendritic cells but that LLT1 is up-regulated upon activation. Not only TLR-stimulated dendritic cells and B cells but also T cell receptor-activated T cells and activated NK cells up-regulate LLT1. Interestingly, IFN-γ increases LLT1 expression level on antigen-presenting cells. LLT1 is also induced on B cells upon viral infection such as Epstein-Barr virus or HIV infection and in inflamed tonsils. Finally, expression of LLT1 on B cells inhibits NK cell function but costimulates T cell proliferation or IFN-γ production, and coengagement of CD161 with CD3 increases IL-17 secretion. Altogether, our results point toward a role for LLT1/CD161 in modulating immune responses to pathogens.

Highlights

CD161 expressed by natural killer (NK) cells and T cells interacts with Lectin-like transcript 1 (LLT1)
We could detect intracellular LLT1 protein expression in IL-2-activated polyclonal NK cell lines generated in the presence of allogeneic Peripheral Blood Mononuclear Cells (PBMCs) and B cells by Western blotting (Fig. 2E), but cell surface expression was detected only on NK cells incubated for 18 h with some but not all NK-sensitive targets (Fig. 2F, upper)
Because NK cell activation results from a balance between the engagement of activating and inhibitory receptors, whose ligands can be differentially expressed on target cells, we tested whether LLT1 expression required the engagement of specific NK receptors

Summary

Background

Results: LLT1 expression profile reveals LLT1 is induced by pathogens and IFN-␥ and LLT1/CD161 interaction inhibits NK cell functions whereas it costimulates T cells. Lectin-like transcript 1 (LLT1), the ligand of CD161, was found to be expressed on Toll-like receptor (TLR)-activated plasmacytoid and monocyte-derived dendritic cells (DC) and on activated B cells. Expression of LLT1 on B cells inhibits NK cell function but costimulates T cell proliferation or IFN-␥ production, and coengagement of CD161 with CD3 increases IL-17 secretion. It has clearly been established that the LLT1/CD161 interaction inhibits NK cell-mediated cytotoxicity and IFN-␥ secretion [10, 13], but its role on T cells remains controversial. Functional studies with LLT1-expressing B cells demonstrated that the LLT1/CD161 interaction inhibited NK cell function and costimulated proliferation and IFN-␥ secretion by CD161ϩ T cells. LLT1/CD161 represents an additional ligand/receptor pair that regulates both innate and adaptive immune responses

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION