Polyfunctional natural killer cells with a low activation profile in response to Toll-like receptor 3 activation in HIV-1-exposed seronegative subjects

Josenilson F Lima,Maria N Sato,Luanda M S Oliveira,Nátalli Z Pereira,Alberto J S Duarte

doi:10.1038/s41598-017-00637-3

Josenilson F Lima, Maria N Sato + Show 3 more

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https://doi.org/10.1038/s41598-017-00637-3

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Journal: Scientific Reports	Publication Date: Apr 3, 2017
Citations: 21	License type: open-access

Affiliation: Universidade de São Paulo

Abstract

Natural killer (NK) cells are the main mediator of the cytotoxic response in innate immunity and may be involved in resistance to HIV-1 infection in exposed seronegative (ESN) individuals. Toll-like receptor (TLR) signalling is crucial for NK cell activation. Here, we investigated the polyfunctional NK cell response to TLR3 activation in serodiscordant couples. ESN subjects showed increased IFN-γ and CD107a expression in both NK subsets, CD56bright and CD56dim cells, in response to stimulation with a TLR3 agonist, while expression was impaired in the HIV-1-infected partners. TLR3-induced expression of IFN-γ, TNF and CD107a by polyfunctional CD56bright NK cells was more pronounced in ESN individuals than that in healthy controls. Activated NK cells, as determined by CD38 expression, were increased only in the HIV-1-infected partners, with reduced IFN-γ and CD107a expression. Moreover, CD38+ NK cells of the HIV-1-infected partners were associated with increased expression of inhibitory molecules, such as NKG2A, PD-1 and Tim-3, while NK cells from ESN subjects showed decreased NKG2A expression. Altogether, these findings indicate that NK cells of ESN individuals were highly responsive to TLR3 activation and had a polyfunctional NK cell phenotype, while the impaired TLR3 response in HIV-1-infected partners was associated with an inhibitory/exhaustion NK cell phenotype.

Highlights

Some individuals remain HIV-1-seronegative despite repeated unprotected exposure to the virus[1]
We evaluated the TLR3-induced activation of Natural killer (NK) cells and assessed CD62L and CD38 expression in NK cell subsets to verify the polyfunctional response of NK cells in exposed seronegative (ESN) individuals and their HIV-1-infected partners
These findings demonstrate that TLR3 activation enhanced the polyfunctional CD56bright NK cell response in ESN individuals, principally with respect to CD62L+ cells, in contrast to the reduced NK cell function observed in HIV1-infected partners (Fig. 3B)

Summary

Introduction

Some individuals remain HIV-1-seronegative despite repeated unprotected exposure to the virus[1]. Increased natural killer (NK) cell activity has been correlated with protection from infection in several high-risk cohorts of ESN subjects, a finding that suggests the involvement of the innate immune response in resistance to HIV-1 infection[4]. The L-selectin molecule (CD62L) mediates homing of leukocytes to lymphoid organs, and CD56dimCD62L+ cells represent a unique subset of mature, polyfunctional NK cells that affect the magnitude of the local NK cell response to murine viral infection[7, 10] These polyfunctional cells have the ability www.nature.com/scientificreports/. The absence of human leukocyte antigen (HLA) binding to inhibitory killer-cell immunoglobulin-like receptors (KIRs), including KIR2DL2, KIR2DL3 and KIR3DL1, leads to a reduced activation threshold of NK cells from ESN individuals and has been associated with resistance to HIV-1 infection[13]. The expression of Tim-3, a type I transmembrane protein, has been implicated both in activation and inhibition of immune responses[19, 20], in the induction of apoptosis of Tim-3–bearing cells through interactions with galectin-921 and suppression of cell-mediated cytotoxicity[22]

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