CD4(+) T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-alpha/Tumor Necrosis Factor Receptor 1-Dependent

  1. popescu, iulia ORCID logo
  2. Snyder, Mark ORCID logo
  3. Iasella, Carlo J.
  4. Hannan, Stefanie J.
  5. Koshy, Ritchie
  6. Burke, Robin
  7. Das, Antu
  8. Brown, Mark J.
  9. Lyons, Emiliy J.
  10. Lieber, Sophia C.
  11. Chen, Xiaoping
  12. Sembrat, John C.
  13. Bhatt, Payal
  14. Deng, Evan
  15. An, Xiaojing
  16. Linstrum, Kelsey
  17. Kitsios, Georgios
  18. Konstantinidis, Ioannis
  19. Saul, Melissa
  20. Kass, Daniel ORCID logo
  21. Alder, Jonathan K.
  22. Chen, Bill B.
  23. Lendermon, Elizabeth A.
  24. Kilaru, Silpa
  25. Johnson, Bruce
  26. Pilewski, Joseph M.
  27. Kiss, Joseph E.
  28. Wells, Alan H.
  29. Morris, Alison
  30. McVerry, Bryan J.
  31. McMahon, Deborah K.
  32. Triulzi, Darrell J.
  33. Chen, Kong
  34. Sanchez, Pablo G.
  35. McDyer, John F. ORCID logo

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1000 Titel
  • CD4(+) T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-alpha/Tumor Necrosis Factor Receptor 1-Dependent
1000 Autor/in
  1. popescu, iulia |
  2. Snyder, Mark |
  3. Iasella, Carlo J. |
  4. Hannan, Stefanie J. |
  5. Koshy, Ritchie |
  6. Burke, Robin |
  7. Das, Antu |
  8. Brown, Mark J. |
  9. Lyons, Emiliy J. |
  10. Lieber, Sophia C. |
  11. Chen, Xiaoping |
  12. Sembrat, John C. |
  13. Bhatt, Payal |
  14. Deng, Evan |
  15. An, Xiaojing |
  16. Linstrum, Kelsey |
  17. Kitsios, Georgios |
  18. Konstantinidis, Ioannis |
  19. Saul, Melissa |
  20. Kass, Daniel |
  21. Alder, Jonathan K. |
  22. Chen, Bill B. |
  23. Lendermon, Elizabeth A. |
  24. Kilaru, Silpa |
  25. Johnson, Bruce |
  26. Pilewski, Joseph M. |
  27. Kiss, Joseph E. |
  28. Wells, Alan H. |
  29. Morris, Alison |
  30. McVerry, Bryan J. |
  31. McMahon, Deborah K. |
  32. Triulzi, Darrell J. |
  33. Chen, Kong |
  34. Sanchez, Pablo G. |
  35. McDyer, John F. |
1000 Erscheinungsjahr 2022
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2022-06
1000 Erschienen in
1000 Quellenangabe
  • 205(12):1403-1418
1000 Copyrightjahr
  • 2022
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1164/rccm.202111-2493OC |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875894/ |
1000 Ergänzendes Material
  • https://www.atsjournals.org/doi/suppl/10.1164/rccm.202111-2493OC |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • RATIONALE: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. OBJECTIVES: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. METHODS: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. MEASUREMENTS AND MAIN RESULTS: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4(+) lymphopenia predominated, with lower CD4(+)/CD8(+) ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4(+) T-cell responses to Spike-1 (S1) produced increased in vitro TNF-alpha (tumor necrosis factor-alpha) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4(+) TNF-alpha(+) T-cell responses inversely correlated with absolute CD4(+) counts from patients with severe COVID-19 (n = 76; R = - 0.797; P < 0.0001). In vitro TNF-alpha blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4 (+) T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFKB signaling in S1-stimulated CD4(+) cells with infliximab treatment. We also evaluated BAL and lung explant CD4(+) T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-alpha compared with peripheral blood mononuclear cells. CONCLUSIONS: Together, our findings show CD4(+) dysfunction in severe COVID-19 is TNF-alpha/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-alpha blockade may be beneficial in severe COVID-19.
1000 Sacherschließung
gnd 1206347392 COVID-19
lokal SARS-CoV-2-infection
lokal TNF-α
lokal lymphopenia
lokal CD41 T cells
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0003-4294-1223|https://orcid.org/0000-0002-0092-9296|https://frl.publisso.de/adhoc/uri/SWFzZWxsYSwgQ2FybG8gSi4g|https://frl.publisso.de/adhoc/uri/SGFubmFuLCBTdGVmYW5pZSBKLg==|https://frl.publisso.de/adhoc/uri/S29zaHksIFJpdGNoaWU=|https://frl.publisso.de/adhoc/uri/QnVya2UsIFJvYmlu|https://frl.publisso.de/adhoc/uri/RGFzLCBBbnR1|https://frl.publisso.de/adhoc/uri/QnJvd24sIE1hcmsgSi4=|https://frl.publisso.de/adhoc/uri/THlvbnMsIEVtaWxpeSBKLg==|https://frl.publisso.de/adhoc/uri/TGllYmVyLCBTb3BoaWEgQy4=|https://frl.publisso.de/adhoc/uri/Q2hlbiwgWGlhb3Bpbmc=|https://frl.publisso.de/adhoc/uri/U2VtYnJhdCwgSm9obiBDLg==|https://frl.publisso.de/adhoc/uri/QmhhdHQsIFBheWFs|https://frl.publisso.de/adhoc/uri/RGVuZywgRXZhbg==|https://frl.publisso.de/adhoc/uri/QW4sIFhpYW9qaW5n|https://frl.publisso.de/adhoc/uri/TGluc3RydW0sIEtlbHNleQ==|https://frl.publisso.de/adhoc/uri/S2l0c2lvcywgR2Vvcmdpb3M=|https://frl.publisso.de/adhoc/uri/S29uc3RhbnRpbmlkaXMsIElvYW5uaXM=|https://frl.publisso.de/adhoc/uri/U2F1bCwgTWVsaXNzYQ==|https://orcid.org/0000-0001-6597-7830|https://frl.publisso.de/adhoc/uri/QWxkZXIsIEpvbmF0aGFuIEsu|https://frl.publisso.de/adhoc/uri/Q2hlbiwgQmlsbCBCLg==|https://frl.publisso.de/adhoc/uri/TGVuZGVybW9uLCBFbGl6YWJldGggQS4=|https://frl.publisso.de/adhoc/uri/S2lsYXJ1LCBTaWxwYQ==|https://frl.publisso.de/adhoc/uri/Sm9obnNvbiwgQnJ1Y2U=|https://frl.publisso.de/adhoc/uri/UGlsZXdza2ksIEpvc2VwaCBNLg==|https://frl.publisso.de/adhoc/uri/S2lzcywgSm9zZXBoIEUu|https://frl.publisso.de/adhoc/uri/V2VsbHMsIEFsYW4gSC4=|https://frl.publisso.de/adhoc/uri/TW9ycmlzLCBBbGlzb24=|https://frl.publisso.de/adhoc/uri/TWNWZXJyeSwgQnJ5YW4gSi4=|https://frl.publisso.de/adhoc/uri/TWNNYWhvbiwgRGVib3JhaCBLLg==|https://frl.publisso.de/adhoc/uri/VHJpdWx6aSwgRGFycmVsbCBKLg==|https://frl.publisso.de/adhoc/uri/Q2hlbiwgS29uZw==|https://frl.publisso.de/adhoc/uri/U2FuY2hleiwgUGFibG8gRy4=|https://orcid.org/0000-0003-0595-595X
1000 Label
1000 Förderer
  1. David Scaife Foundation |
  2. National Institutes of Health |
  3. Pittsburgh Foundation |
1000 Fördernummer
  1. -
  2. R01 HL133184
  3. -
1000 Förderprogramm
  1. -
  2. -
  3. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer David Scaife Foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer National Institutes of Health |
    1000 Förderprogramm -
    1000 Fördernummer R01 HL133184
  3. 1000 joinedFunding-child
    1000 Förderer Pittsburgh Foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6435476.rdf
1000 Erstellt am 2022-10-12T15:56:58.751+0200
1000 Erstellt von 329
1000 beschreibt frl:6435476
1000 Bearbeitet von 25
1000 Zuletzt bearbeitet 2023-10-20T13:13:55.932+0200
1000 Objekt bearb. Thu Apr 27 12:34:56 CEST 2023
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