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Are T cells helpful for COVID-19: the relationship between response and risk
Diane E. Griffin
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Address correspondence to: Diane E. Griffin, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 USA; Phone: 410.955.3459. Email: dgriffi6@jhu.edu.
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Published September 25, 2020 - More info
J Clin Invest. 2020;130(12):6222–6224. https://doi.org/10.1172/JCI142081.
© 2020 American Society for Clinical Investigation
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Abstract
Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2–specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2–specific CD4+ T cells, harboring higher portions of IL-2–secreting, but lower portions of IFN-γ–secreting, cells. Diminished frequencies of membrane protein–reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2–specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2–specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.
Authors
Arne Sattler, Stefan Angermair, Helena Stockmann, Katrin Moira Heim, Dmytro Khadzhynov, Sascha Treskatsch, Fabian Halleck, Martin E. Kreis, Katja Kotsch
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Are T cells helping?
CD4+ Th cells are functionally diverse. Several subsets have been defined by transcription factor and cytokine and chemokine expression, but there is substantial plasticity, and overlapping phenotypes are common (19, 20). Th1 cells expressing IFN-γ, TNF-α, and IL-2 are classically considered most important for the response to intracellular pathogens, including viruses. However, virus infections induce many other types of CD4+ T cells with relevant functions (21). For instance, Th2 cells expressing IL-4, IL-5, and IL-13 provide help for B cell proliferation. Th17 cells expressing IL-17 and IL-22 can act pathogenic or regulatory depending in part on whether they also produce IFN-γ or IL-10. T follicular helper (Tfh) cells express IL-21 to promote germinal center formation for maturation of antibody-secreting cells. Regulatory T cells express IL-10. All of these lineages can be identified in peripheral blood in varying proportions during the response to infection, although the primary sites of function are in lymphoid tissues and at sites of virus replication.
In this issue of the JCI, Sattler and Angermair et al. (22) used flow cytometry analysis of PBMCs to examine the CD4+ T cell responses to stimulation with overlapping peptides from SARS–CoV-2 S, M, and N proteins for 39 hospitalized patients stratified by intensive care unit status and seven nonhospitalized patients recovered from mild disease. Virus-specific T cells, as identified by surface expression of activation markers after stimulation in culture with viral peptides, were present in most acutely ill hospitalized patients and comparable numbers of CD4+ T cells responded to peptides from each of the proteins (22).
Patients who failed to mount a CD4+ T cell response (nonresponders) were primarily in the group sampled early in their disease course. While these subjects showed similar T cell numbers with those who successfully mounted a T cell response (responders), S, M, and N failed to stimulate the T cells themselves (22). An early deficiency in CD4+ T cell response is consistent with the previously reported two-week time frame of symptom onset, and for the development of the CD4+ T cell response to S (4). The response to S is of particular interest because the spike protein is the viral surface glycoprotein that contains the binding site for the ACE-2 cellular receptor and is the target for neutralizing antibodies and the focus of most vaccine development efforts. Patients with no evidence of a CD4+ T cell response to S peptides were also negative for IgG antibody to S in serum, suggesting a failure to mount either an effective B cell or T cell adaptive immune response to this viral protein. These nonresponding patients were also most likely to die from COVID-19, further indicating the importance of prompt virus-specific immune responses for recovery (22).
Interestingly, among responding patients, higher CD4+ T cell responses to all three proteins were associated with older age, higher comorbidity indices, and more severe disease with the most substantial differences in responses to M. To determine the functional capacity of the CD4+ T cells responding to each of the viral proteins, Sattler, Angermair, and colleagues measured IL-2, TNF-α, and IFN-γ production. N-specific cells were least likely, and M-specific T cells were most likely, to produce IFN-γ alone or in combination with TNF-α. In addition to antigen-specific differences in function, differences among patient groups were also evident. In older patients with higher comorbidity indices, even though there were larger numbers of cells, activated cells were less likely to secrete IFN-γ and more likely to produce IL-2 (Figure 1). However, differences between patients with different levels of disease severity were not evident (22). This relationship contrasts with earlier studies of CD4+ T cell function that identified lower percentages of cells producing IFN-γ in severely ill patients compared with those having mild disease, though viral protein specificity was not determined (14).
Figure 1Model for T cell response in COVID-19 relative to patient risk. Patients at risk for severe COVID-19 disease (advanced age and higher comorbidity) show higher T cell responses than those at low risk. However, the activated T cells from patients at risk have impaired IFN-γ and enhanced IL-2 production.
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