TNF-α+ CD4+ T cells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies

Kattria van der Ploeg; Adam S Kirosingh; Diego A M Mori; Saborni Chakraborty; Zicheng Hu; Benjamin L Sievers; Karen B Jacobson; Hector Bonilla; Julie Parsonnet; Jason R Andrews; Kathleen D Press; Maureen C Ty; Daniel R Ruiz-Betancourt; Lauren de la Parte; Gene S Tan; Catherine A Blish; Saki Takahashi; Isabel Rodriguez-Barraquer; Bryan Greenhouse; Upinder Singh; Taia T Wang; Prasanna Jagannathan

doi:10.1016/j.xcrm.2022.100640

TNF-α⁺ CD4⁺ T cells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies

Cell Rep Med. 2022 Jun 21;3(6):100640. doi: 10.1016/j.xcrm.2022.100640. Epub 2022 May 3.

Authors

Kattria van der Ploeg¹, Adam S Kirosingh², Diego A M Mori¹, Saborni Chakraborty¹, Zicheng Hu³, Benjamin L Sievers⁴, Karen B Jacobson¹, Hector Bonilla¹, Julie Parsonnet⁵, Jason R Andrews¹, Kathleen D Press¹, Maureen C Ty¹, Daniel R Ruiz-Betancourt¹, Lauren de la Parte¹, Gene S Tan⁶, Catherine A Blish⁷, Saki Takahashi⁸, Isabel Rodriguez-Barraquer⁸, Bryan Greenhouse⁹, Upinder Singh¹⁰, Taia T Wang¹⁰, Prasanna Jagannathan¹¹

Affiliations

¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
³ Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143, USA.
⁴ J. Craig Venter Institute, La Jolla, CA 92037, USA.
⁵ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Epidemiology and Population Health, Stanford University, Stanford, CA 94305, USA.
⁶ J. Craig Venter Institute, La Jolla, CA 92037, USA; Division of Infectious Disease, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁷ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁸ Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
⁹ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
¹⁰ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
¹¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4⁺ T cells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4⁺ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4⁺ T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4⁺ response shifts from cells producing interferon gamma (IFNγ) to tumor necrosis factor alpha (TNF-α) from 5 days to 4 months post-enrollment, with IFNγ^-IL-21^-TNF-α⁺ CD4⁺ T cells the predominant population detected at later time points. Greater percentages of IFNγ^-IL-21^-TNF-α⁺ CD4⁺ T cells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7 months post-infection (⍴ = 0.4, p = 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ- and TNF-α-producing, spike-protein-specific CD4⁺ T cells. These data suggest that SARS-CoV-2-specific, TNF-α-producing CD4⁺ T cells may play an important role in antibody maintenance following COVID-19.

Trial registration: ClinicalTrials.gov NCT04331899.

Keywords: CD4; COVID-19; SARS-CoV-2; T cells; TNF-α; Tfh; antibodies; cytokines; longitudinal; neutralizing antibodies.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antibodies, Neutralizing
CD4-Positive T-Lymphocytes
COVID-19*
Humans
Outpatients
SARS-CoV-2*
T-Lymphocytes
Tumor Necrosis Factor-alpha

TNF-α⁺ CD4⁺ T cells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies

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