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T Cell Responses in Patients with COVID-19

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T Cell Responses in Patients with COVID-19 PROGRESS typically occurs for only 2–4 days around symptom onset and rapidly recovers15. T cell responses in patients with By contrast, COVID-19- associated lymphopenia may be more severe or COVID-19 persistent than in these other infections and seems to be more selective for T cell lineages. It is possible that the peripheral lymphopenia Zeyu Chen and E. John Wherry observed in patients with COVID-19 reflects Abstract | The role of T cells in the resolution or exacerbation of COVID-19, as well recruitment of lymphocytes to the respiratory as their potential to provide long- term protection from reinfection with tract or adhesion to inflamed respiratory vascular endothelium. However, although SARS- CoV-2, remains debated. Nevertheless, recent studies have highlighted autopsy studies of patients’ lungs and various aspects of T cell responses to SARS-CoV-2 infection that are starting to single- cell RNA sequencing (scRNA-seq) of enable some general concepts to emerge. bronchoalveolar lavage fluid do identify the presence of lymphocytes, the lymphocytic infiltration is not excessive5,16. In addition, COVID-19 caused by SARS-CoV-2 observed in patients with severe disease, a recent scRNA-seq analysis of the upper infection is a global pandemic, with more relevant features of CD8+ versus CD4+ T cell respiratory tract from patients with than 15.8 million infections and more than responses in patients who are hospitalized, COVID-19 showed that there was a markedly 641,000 deaths as of 25 July 2020, according features of T cell differentiation that may decreased contribution of cytotoxic T to the COVID-19 Map of the Johns Hopkins be altered and current data on whether the lymphocytes in patients with severe disease Coronavirus Resource Center. SARS- CoV-2 overall magnitude of the T cell response in compared with those with moderate disease9. infection can result in a range of clinical patients with COVID-19 is insufficient or In severe disease, lymphopenia may be manifestations, from asymptomatic or excessive and how these features may relate associated with high levels of IL-6, IL-10 or mild infection to severe COVID-19 that to disease. Finally, we discuss emerging tumour necrosis factor (TNF)6,10,14, potentially requires hospitalization. Patients who data on SARS-CoV-2- specific T cells through a direct effect of these cytokines on are hospitalized often progress to severe found in patients who have recovered from T cell populations17,18 and/or indirect effects pneumonia and acute respiratory distress COVID-19 and the implications for T cell via other cell types, such as dendritic cells19 syndrome (ARDS)1–3. Although relatively memory. In this rapidly emerging field, and neutrophils20,21. Hyperactivation of T cells little is known about the immunology we summarize the most recent studies or high levels of expression of pro-apoptotic of individuals who are asymptomatic or that have addressed T cell responses in molecules, such as FAS (also known as individuals with mild disease who do not COVID-19. Some of these are as yet only CD95)8, TRAIL or caspase 3 (REF.11), could require hospitalization, recent studies have available on preprint servers and conclusions also contribute to T cell depletion. revealed important insights into the immune from non- peer- reviewed data should be Thus, although the mechanisms of responses of patients who are hospitalized. treated with caution. A summary of the data lymphopenia in COVID-19 remain Similar to other respiratory viral infections, sets that are published versus those available incompletely understood, the reduction in adaptive immune responses4–9, particularly as preprints is provided in Table 1 to aid the the number of T cells, in particular, in the of T cells6,8,10, have a prominent role in reader in establishing the weight of evidence periphery is a prominent feature of many SARS- CoV-2 infection. However, it remains for particular features. individuals with severe disease. It remains unclear whether T cell responses are helpful unclear why the lymphopenia is T cell or harmful in COVID-19, and whether T cell Lymphopenia in COVID-19 biased and perhaps specifically CD8+ responses are suboptimal and dysfunctional One prominent feature of SARS-CoV-2 T cell biased. In animal models, lymphopenia or excessive, with evidence having been infection is lymphopenia1,6,12,13. Lymphopenia can augment T cell activation and provided for both ends of the spectrum. is associated with severe disease10,12,13 but is proliferation22. Therefore, determining how Here, we summarize some of the recent reversed when patients recover4,12. In some lymphopenia in patients with COVID-19 data on conventional T cell responses patients, lymphopenia has been reported might impact T cell hyperactivation in COVID-19, noting, however, that to affect CD4+ T cells, CD8+ T cells, B cells and, potentially, immunopathology is an emerging data also highlight impacts on and natural killer cells4,6, whereas other data important future goal, as therapeutics such other lymphocyte populations, including suggest that SARS-CoV-2 infection has a as IL-7 could be beneficial in this regard. B cells4,8,11, innate lymphoid cells4, natural preferential impact on CD8+ T cells8,9,14. killer cells4,11, mucosa- associated invariant Transient lymphopenia is a common feature CD8+ T cell responses in COVID-19 T cells4 and γδT cells11. We highlight some of of many respiratory viral infections, such Early studies of small numbers of patients, the key observations made for conventional as with influenza A H3N2 virus, human or sometimes even a single patient, reported αβ CD8+ and CD4+ T cells in COVID-19, rhinovirus or respiratory syncytial virus, alterations in the activation and/or including the prominent lymphopenia but lymphopenia in these other infections differentiation status of CD8+ T cells in NATURE REVIEWS | IMMUNOLOGY VOLUME 20 | SEPTEMBER 2020 | 529 PROGRESS Table 1 | Studies reporting T cell analysis in patients with COVID-19 Donor cohort Sample origin Profiling technology Major conclusions for αβT cells Refs used 3 healthy, 3 mild/ Bronchoalveolar 10x Genomics Greater clonal expansion of T cells in moderate disease than severe 5 moderate disease, lavage fluid scRNA- seq, 10× disease; T cells in moderate disease have stronger signatures of tissue 6 severe disease Genomics scTCR-seq residency 8 moderate disease, Nasopharyngeal 10x Genomics Fewer CTLs in severe disease than moderate disease; hyperactivation of 9 11 severe disease and bronchial scRNA- seq CTLs in the respiratory tract, with a signature of interacting with epithelial samples cells and other immune cell types 5 healthy, PBMCs 10x Genomics Greater clonal expansion of T cells in late-recovered than in early- 28 5 early- recovered, scRNA- seq, 10x recovered patients; fewer CD8+ T cells but greater cytotoxic signatures 5 late- recovered Genomics scTCR-seq in early-recovered than in late-recovered patients 6 healthy, PBMCs Seq- Well scRNA-seq Heterogeneity of immune responses, including of interferon-stimulated 7 3 non-ventilated, genes; no transcriptional signature of exhaustion; features of T cell 4 with ARDS hyperactivation in some of the patients with ARDS 3 healthy, 6 mild/ PBMCs 10x Genomics Strong T cell lymphopenia in severe disease with potential systemic 25 moderate disease, scRNA- seq, flow adaptive immune dysregulation; altered T cell differentiation and a (Preprint) 4 severe disease cytometry hyperactivation stage in severe disease; thymosin α1 can expand the memory- like T cell population and prevent T cell hyperactivation 15 healthy, PBMCs 10x Genomics Similar total and activated T cell counts for influenza and COVID-19 40 79 COVID-19 scRNA- seq (3 groups; higher IFNα- responding and IFNγ- responding signatures in the (Preprint) (15 with ARDS), influenza and 4 severe influenza groups than in the COVID-19 groups 26 influenza COVID-19), (7 with ARDS) flow cytometry 28 with ARDS, PBMCs Flow cytometry Stronger T cell lymphopenia in more severe COVID-19; lower CD4+ T cell 6 26 non-ARDS, other counts in COVID-19 (n = 17) than in influenza (H1N1; n = 4) infection controls 12 healthy, PBMCs High- dimensional Stronger T cell lymphopenia in more severe disease; heterogeneity of 4 7 recovered, flow cytometry T cell responses related to activation and cytotoxicity signatures; T cells 7 moderate disease, express more markers of terminal differentiation or exhaustion in severe 27 severe disease disease 60 healthy, PBMCs High- dimensional Stronger T cell lymphopenia in severe disease, with a bias towards CD8+ 8 36 recovered, flow cytometry T cells; heterogeneity of T cell responses based on high-dimensional 125 hospitalized immune profiling, with three potential immune subtypes; T cells more patients (NIH activated but also express more markers of terminal differentiation ordinal score 2–5) and exhaustion in patients with COVID-19 than in individuals who are healthy or who recovered 40 healthy, 522 with PBMCs Flow cytometry Stronger T cell lymphopenia in ICU patients, elderly patients and severe 10 varying disease disease, for both CD4+ and CD8+ T cells; IL-6, IL-10 and TNF levels severity negatively correlate with lymphocyte count; T cells express higher levels of PD1 and TIM3 in ICU patients than in non-ICU individuals 55 healthy, PBMCs High- dimensional Stronger T cell lymphopenia in severe disease; increased number of 11 6 mild disease, flow cytometry hyperactivated proliferating CD4+ and CD8+ T cells in severe disease; (Preprint) 26 moderate increased markers of terminal
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