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Two Studies Chart Robust CD4 T-cell Responses to COVID-19 Virus
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Mark Mascolini
Researchers in the United States and Germany independently identified strong CD4 T-cell responses to SARS-CoV-2, the virus that causes COVID-19, in a large majority of tested individuals who had recovered from COVID-19 [1,2]. In both studies a smaller proportion of people who never had COVID-19 also had T cells reactive to SARS-CoV-2, a finding suggesting that some T cells that recognize common-cold coronaviruses also recognize SARS-CoV-2. Results of these studies do not say whether people who recover from COVID-19 can fight off later SARS-CoV-2 infections because of these T-cell responses.
The US study led by Alessandro Sette and Shane Crotty of the La Jolla Institute for Immunology involved 20 adults who had COVID-19 and 20 who did not [1]. Median age stood at 44 in the COVID-19 group (range 20 to 64) and 31 in the non-COVID group (range 20 to 66). Among people with COVID-19, 55% were women, 70% had mild disease, 20% moderate disease, and 10% severe disease. No one had critical disease.
All 20 COVID-19 participants and half of the non-COVID group had CD4 T cells reactive to SARS-CoV-2 in peripheral blood mononuclear cells (PBMCs). While 70% of COVID-19 participants had CD8 cells reactive to SARS-CoV-2, 20% of the non-COVID group had reactive CD8 cells.
CD4 responses to the SARS-CoV-2 spike protein, which the virus uses to snare target cells, were robust and correlated with levels of anti-SARS-CoV-2 IgG and IgA. T cells also reacted to SARS-CoV-2 proteins M, N, nsp3, nsp4, ORF3a, ORF8, and others. The researchers believe the SARS-CoV-2-crossreactive T-cell responses seen in healthy people indicate "some potential for pre-existing immunity in the human population."
The German study headed by Andreas Thiel at Berlin's Charité University Hospital appeared as a preprint that has not had peer review [2]. It involved 18 people who had recovered from COVID-19 and 68 healthy donors. Among the COVID-19 participants, age averaged 52.6 (range 21 to 81), 72% were men, 39% had mild disease, 28% had severe disease, 33% had critical disease, and 55.6% needed intensive care unit (ICU) support.
In the COVID-19 group a big majority, 83%, had peripheral blood CD4 T cells reactive to the spike protein of SARS-CoV-2, as did 34% of healthy controls. Compared with spike-reactive T cells of the control group, those in people who recovered from COVID-19 had higher levels of CD38 and HLA-DR, which suggested recent activation in these individuals.
While spike-reactive T cells of COVID-19 participants equally targeted N-terminal and C-terminal epitopes of spike, T cells from healthy donors reacted almost exclusively with C-terminal epitopes, which look more like the spike protein of common-cold coronaviruses. (Epitopes are the part of antigen molecule to which an antibody attaches itself.) SARS-CoV-2 cross-reactive T cells in one third of healthy controls, the German team writes, "may represent the key to understanding the vastly divergent manifestations of SARS-CoV-2 disease courses, and particularly the suspected high rate of asymptomatic infections in children and young adults" [2]. Because children and young adults have more frequent social contacts than the elderly, they surmise, "one might expect a higher [common-cold coronavirus] transmission rate and prevalence" in younger people. But the German researchers cautioned that larger prospective studies are needed to determine whether reactive T cells in people who never had COVID-19 are "a correlate of protection or pathology."
Interviewed in a review of these studies in Science, University of North Carolina molecular virologist Rachel Graham observed that the results have implications for SARS-CoV-2 vaccine development [3]. Most vaccines being tested now target the viral spike protein. But the US study [1] shows that T cells react to several SARS-CoV-2 proteins. "It is important to not just concentrate on one protein," Graham told Science, because vaccines that target several viral proteins could be more effective.
References
1. Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020. doi: https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3
2. Braun J, Loyal L, Frentsch M, et al. Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors. medRxiv. doi: https://doi.org/10.1101/2020.04.17.20061440 (This article is a preprint that has not had peer review.)
3. Leslie M. T cells found in COVID-19 patients 'bode well' for long-term immunity. Science. May. 14, 2020. https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity?utm
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