Human MAIT cells respond to and suppress HIV-1
- University of Oxford, United Kingdom
- Imperial College London, United Kingdom
- University of New South Wales, Australia
- Military Hospital, South Africa
- University of the Free State, South Africa
- The University of Queensland, Australia
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 up-regulate granzyme B, IFNg 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.
Data availability
Raw data from main figures are provided as source data files.
Article and author information
Author details
Chansavath Phetsouphanh
Quentin J Sattentau
Funding
Wellcome Trust (WT109965MA)
- Paul Klenerman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stipan Jonjic, University of Rijeka, Croatia
Ethics
Human subjects: The SPARTAC trial (EudraCT Number: 2004-000446-20) was approved by the following authorities: the Medicines and Healthcare products Regulatory Agency (UK), the Ministry of Health (Brazil), the Irish Medicines Board (Ireland), the Medicines Control Council (South Africa) and the Uganda National Council for Science and Technology (Uganda). It was also approved by the following ethics committees in the participating countries: the Central London Research Ethics Committee (UK), Hospital Universitário Clementino Fraga Filho Ethics in Research Committee (Brazil), the Clinical Research and Ethics Committee of Hospital Clinic in the province of Barcelona (Spain), the Adelaide and Meath Hospital Research Ethics Committee (Ireland), the University of Witwatersrand Human Research Ethics Committee, the University of Kwazulu-Natal Research Ethics Committee and the University of Cape Town Research Ethics Committee (South Africa), Uganda Virus Research Institute Science and ethics committee (Uganda), the Prince Charles Hospital Human Research Ethics Committee and St Vincent's Hospital Human Research Ethics Committee (Australia) and the National Institute for Infectious Diseases Lazzaro Spallanzani, Institute Hospital and the Medical Research Ethics Committee, and the ethical committee of the Central Foundation of San Raffaele, MonteTabor (Italy).Recruitment for and studies within the HEATHER cohort were approved by the West Midlands-South Birmingham Research Ethics Committee (reference 14/WM/1104). Recruitment of CHI participants were approved by The University of the Free State Ethics Committee (ETOVS 171/08). LTNPs recruitment was approved by The St Vincent's Human Research Ethics Committee (EC00140) approval number: HREC/12/SVH/298, SVH 12/217. PBMCs obtained from healthy donors were approved by the Sheffield Research Ethics Committee (reference 16/YH/0247). Participants were aged 18 years or older, all participants from each of the above mentioned cohorts gave informed and written consent for their participation in these studies.
Version history
- Received: July 18, 2019
- Accepted: December 23, 2021
- Accepted Manuscript published: December 24, 2021 (version 1)
- Version of Record published: January 11, 2022 (version 2)
Copyright
© 2021, Phetsouphanh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,249
- views
-
- 207
- downloads
-
- 14
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Human MAIT cells respond to and suppress HIV-1
eLife 10:e50324.
https://doi.org/10.7554/eLife.50324
Further reading
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
-
- Genetics and Genomics
- Immunology and Inflammation
Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
