Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection
- University of Massachusetts Medical School, United States
- Ragon Institute of MGH, MIT and Harvard, United States
- Massachusetts General Hospital, United States
- University of Pennsylvania, United States
- Brigham and Women's Hospital, United States
- Ragon Institute of MGH, MIT, and Harvard, United States
Abstract
Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations.
Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n=40), treated for COVID-19 as outpatients (n=51), and in uninfected controls (n=86), as well as in children with COVID-19 (n=19), recovering from COVID-19 (n=14), MIS-C (n=11), recovering from MIS-C (n=7), and pediatric controls (n=17).
Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls.
Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males.
Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.
Data availability
All clinical and flow cytometry data generated and analyzed in this article are included in the manuscript and are provided in three spreadsheets titled: "Adult_COVIDandControl_data.xlsx", "Pediatric_ COVID_MISC_andControl_data.xlsx", and "AREG_in_ILCs.xlsx". New Bulk RNA-seq datasets generated here are deposited at: NCBI Gene Expression Omnibus (GEO): GSE168212.
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Systematic analysis of innate lymphoid cells and natural killer cells in context of HIV-1 infectionNCBI Gene Expression Omnibus, GSE168212.
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Group 3 innate lymphoid cells mediate early protective immunity against Mycobacterium tuberculosisNCBI Gene Expression Omnibus, GSE131031.
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Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue SpecificityNCBI Gene Expression Omnibus, GSE126107.
Article and author information
Author details
Noah J Silverstein
Funding
National Institutes of Health (R37AI147868)
- Jeremy Luban
National Institutes of Health (R01AI148784)
- Jeremy Luban
National Institutes of Health (F30HD100110)
- Noah J Silverstein
National Institutes of Health (5K08HL143183)
- Lael M Yonker
Massachusetts Consortium for Pathogen Readiness
- Jeremy Luban
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece
Ethics
Human subjects: As part of a COVID-19 observational study, peripheral blood samples were collected between March 31st and June 3rd of 2020 from 91 adults with SARS-CoV-2 infection, either after admission to Massachusetts General Hospital for the hospitalized cohort, or while at affiliated outpatient clinics for the outpatient cohort. Request for access to coded patient samples was reviewed by the Massachusetts Consortium for Pathogen Readiness (https://masscpr.hms.harvard.edu/) and approved by the University of Massachusetts Medical School IRB (protocol #H00020836). Pediatric participants with COVID-19 or MIS-C were enrolled in the Massachusetts General Hospital Pediatric COVID-19 Biorepository (MGB IRB # 2020P000955). Healthy pediatric controls were enrolled in the Pediatric Biorepository (MGB IRB # 2016P000949). Samples were collected after obtaining consent from the patient if 18 years or older, or from the parent/guardian, plus assent when appropriate.
Version history
- Preprint posted: January 15, 2021 (view preprint)
- Received: October 14, 2021
- Accepted: March 11, 2022
- Accepted Manuscript published: March 11, 2022 (version 1)
- Version of Record published: April 25, 2022 (version 2)
Copyright
© 2022, Silverstein 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.
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Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection
eLife 11:e74681.
https://doi.org/10.7554/eLife.74681
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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.
