Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19

Immunity. 2020 Dec 15;53(6):1258-1271.e5. doi: 10.1016/j.immuni.2020.11.016. Epub 2020 Nov 26.


CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

Keywords: ARTE; COVID-19; SARS-CoV-2; T cell cross-reactivity; antigen-reactive T cell enrichment; antigen-specific T cells; common cold coronavirus; human coronavirus; pre-existing memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • COVID-19 / immunology*
  • Cells, Cultured
  • Cross Reactions
  • Disease Progression
  • Environmental Exposure
  • Humans
  • Immunologic Memory
  • Lymphocyte Activation
  • Protein Binding
  • Receptors, Antigen, T-Cell / metabolism*
  • Rhinovirus / immunology*
  • SARS-CoV-2 / immunology*
  • Severity of Illness Index
  • T-Cell Antigen Receptor Specificity


  • Antigens, Viral
  • Receptors, Antigen, T-Cell