Human MAIT cells respond to and suppress HIV-1.

Chansavath Phetsouphanh,Prabhjeet Phalora,Carl-Philipp Hackstein,Rebecca A Russell,Jeffrey Yw Mak,Jodi Meyerowitz,David P Fairlie,Dominique Goedhals,Sarah Fidler,John Frater,Lyle Murray,Cloete Vanvuuren,Anthony D Kelleher,Quentin J Sattentau,C Mee Ling Munier,Linnea Drexhage,Paul Klenerman,John Thornhill

doi:10.7554/elife.50324

Abstract

Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected individuals, which decreased following ART. Stimulation of THP1 monocytes with R5 tropic HIVBAL potently activated MAIT cells in vitro. This activation was dependent on IL-12 and IL-18 but was independent of the TCR. Upon activation, MAIT cells were able to upregulate granzyme B, IFNγ and HIV-1 restriction factors CCL3, 4, and 5. Restriction factors produced by MAIT cells inhibited HIV-1 infection of primary PBMCs and immortalized target cells in vitro. These data reveal MAIT cells to be an additional T cell population responding to HIV-1, with a potentially important role in controlling viral replication at mucosal sites.

Highlights

Mucosal-associated invariant T-cells (MAIT cells) are innate-like T cells that rapidly produce cytokines upon activation and express a semi-invariant T-cell antigen receptor (TCR)(Birkinshaw et al, 2014, Zinser et al, 2018)
While previous experiments showed that HIV-1 infection leads to a decrease of MAIT cells (Cosgrove et al, 2013), it remains to be determined if MAIT cells display any kind of antiviral activity in the context of HIV-1 infection. 83 Here, we investigated to what extent and by which mechanisms HIV-1 could activate MAIT 84 cells and whether this resulted in measurable anti-HIV-1 activity
111 Results 112 113 MAIT cells are activated by HIV-1 in vivo 114 115 To first address MAIT cell activation during HIV-1 infection, PD-1, granzyme B (GzmB), and TIM-3 protein levels were measured pre- and post-Antiretroviral Therapy (ART) in donors with Primary and Chronic HIV-1 infection (PHI and CHI respectively) (Fig. 1A&1B)

Summary

Introduction

Mucosal-associated invariant T-cells (MAIT cells) are innate-like T cells that rapidly produce cytokines upon activation and express a semi-invariant T-cell antigen receptor (TCR)(Birkinshaw et al, 2014, Zinser et al, 2018). 69 70 It has been shown that MAIT cells have the ability to sense viral infections through specific cytokine-driven mechanisms, including IL-12, IL-15, IL-18, Type I interferons (van Wilgenburg et al, 2016b, Ussher et al, 2014) and most recently TNF (Provine et al, 2021) These mechanisms have been defined in vitro and activation of MAIT cells in response to acute and persistent virus infections (Dengue, HCV, and Influenza) and vaccines has been clearly demonstrated in vivo in humans (Wilgenburg et al, 2018, van Wilgenburg et al, 2016a, Loh et al, 2016, Provine et al, 2021).

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