Persistent Antigen Harbored by Alveolar Macrophages Enhances the Maintenance of Lung-Resident Memory CD8+ T Cells [MUCOSAL IMMUNOLOGY]

Abstract

Lung tissue-resident memory T cells are crucial mediators of cellular immunity against respiratory viruses; however, their gradual decline hinders the development of T cell–based vaccines against respiratory pathogens. Recently, studies using adenovirus (Ad)-based vaccine vectors have shown that the number of protective lung-resident CD8+ TRMs can be maintained long term. In this article, we show that immunization of mice with a replication-deficient Ad serotype 5 expressing influenza (A/Puerto Rico/8/34) nucleoprotein (AdNP) generates a long-lived lung TRM pool that is transcriptionally indistinct from those generated during a primary influenza infection. In addition, we demonstrate that CD4+ T cells contribute to the long-term maintenance of AdNP-induced CD8+ TRMs. Using a lineage tracing approach, we identify alveolar macrophages as a cell source of persistent NP Ag after immunization with AdNP. Importantly, depletion of alveolar macrophages after AdNP immunization resulted in significantly reduced numbers of NP-specific CD8+ TRMs in the lungs and airways. Combined, our results provide further insight to the mechanisms governing the enhanced longevity of Ag-specific CD8+ lung TRMs observed after immunization with recombinant Ad.

Footnotes

This work was supported by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) Grant R35HL150803. J.L.L. was supported by NHLBI NIH Grant F31HL156639. We thank the NIH Tetramer Core Facility (Contract 75N93020D00005) for providing class I tetramers. This research project was supported by the Emory University School of Medicine Flow Cytometry Core and the Pediatric/Winship Flow Cytometry Core.

The online version of this article contains supplemental material.

J.L.L. and J.E.K. designed the study; J.L.L. performed experiments with input from I.U., J.M.B., and J.E.K.; J.L.L., C.D.S., and T.M. analyzed the data; J.L.L. wrote the manuscript; and J.M.B., A.R.T., J.P.C., and J.E.K. edited the manuscript.

The sequencing dataset has been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE198980) repository under accession number GSE198980.

Abbreviations used in this article:

AdadenovirusAd-CreAd serotype 5 expressing Cre recombinaseAdNPAd serotype 5 expressing influenza (A/Puerto Rico/8/34) nucleoproteinBALbronchoalveolar lavageCDcluster of differentiationDEGdifferentially expressed gened.p.i.days postinfectioni.n.intranasallyPCAprincipal-component analysisrAdrecombinant Ad vectorSARS-CoV-2severe acute respiratory syndrome coronavirus 2TCMcentral memory T cellTEMeffector memory T cellTRMtissue-resident memory T cellx31influenza A/HKx31x31 NP−x31 NP N370QReceived January 24, 2022.Accepted August 16, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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