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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

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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 differentiation or exhaustion in severe disease, 31 severe disease compared with milder disease disease 10 moderate PBMCs Flow cytometry Higher lymphocyte counts in moderate disease than in severe disease, 13 disease, 11 severe for both CD4+ and CD8+ T cells; more IFNγ-producing​ T cells in moderate disease disease than severe disease 20 healthy, 30 with PBMCs Flow cytometry T cell lymphopenia in patients compared with healthy controls, with 14 varying disease an increased ratio of CD4+ T cells to CD8+ T cells; increased proportion severity of terminally differentiated or senescent CD8+ T cells in patients, with a reduced proportion of IFNγ-producing​ cells; tocilizumab improves lymphocyte counts (n = 5) 30 healthy, 55 mild PBMCs Flow cytometry Stronger T cell lymphopenia in severe disease than in mild disease 23 disease, 13 severe or healthy controls, with recovery of T cell numbers in convalescent disease individuals; reduced levels of multiple cytokines in CD8+ T cells in disease groups, with higher levels of NKG2A expression than healthy controls 6 healthy, 10 mild PBMCs Flow cytometry Increased cytotoxicity but decreased cytokine secretion of T cells, 24 disease, 6 severe particularly CD8+ T cells, in severe disease compared with mild disease; disease CD8+ T cells in severe disease express more inhibitory receptors

+ + 26 Case report, PBMCs Flow cytometry ICOS PD1 circulating TFH cells increase during recovery; activated multiple time points CD4+ and CD8+ T cells peak at day 9 post disease onset and decline after recovery

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Table 1 (cont.) | Studies reporting T cell analysis in patients with COVID-19 Donor cohort Sample origin Profiling technology Major conclusions for αβT cells Refs used 20 healthy, PBMCs Flow cytometry CD4+ and CD8+ T cells from convalescent patients respond to 29 20 convalescent, SARS-​CoV-2 epitopes, including S, M and N proteins and other ORFs; other common cold T cell reactivity to SARS-CoV-2​ also detected in non-exposed​ donors, coronaviruses with potential cross-reactivity​ to other common cold coronaviruses 14 convalescent PBMCs Flow cytometry CD4+ and CD8+ T cells from convalescent patients respond to 30 SARS-​CoV-2 epitopes 16 healthy, PBMCs Flow cytometry T cells from convalescent patients with mild or severe disease respond 31 28 recovered to SARS-CoV-2​ epitopes; convalescent patients with mild disease have (Preprint) from mild disease, a better memory CD8+ T cell response than convalescent patients with 14 recovered from severe disease severe disease 8 healthy, 8 with PBMCs Flow cytometry T cell lymphopenia in COVID-19 compared with healthy controls, with 35 varying disease an increase of T cell activation phenotypes; SARS-CoV-2-​ specific​ T cells

severity mainly produce TH1-​type cytokines 10 healthy, PBMCs Flow cytometry CD4+ T cells in ICU patients produce more GM-CSF​ and IL-6 than 37 21 non-ICU,​ non-ICU​ individuals and healthy controls 12 in ICU 245 healthy, PBMCs Flow cytometry Stronger T cell lymphopenia in severe disease compared with mild 38 19 mild disease, disease and healthy controls; IL-6 levels negatively correlate with 41 severe disease lymphocyte count; patients who respond to treatment recover lymphocyte numbers 15 male and PBMCs High-​dimensional Male and female patients have T cell lymphopenia; female patients 60 29 female healthy, flow cytometry have more T cell activation than male patients; male patients with (Preprint) 17 male and severe disease have greater reduction of T cell activation and loss 21 female with of IFNγ-producers​ than those with stable disease COVID-19 ARDS, acute respiratory distress syndrome; CTL, cytotoxic T lymphocyte; GM-CSF,​ granulocyte–macrophage colony-stimulating​ factor; ICOS, inducible co-stimulator;​ ICU, intensive care unit; IFNγ, interferon-γ​ ; ORF, open reading frame; PBMC, peripheral blood mononuclear cell; PD1, programmed cell death protein 1; scRNA-seq,​ single-​cell RNA sequencing; scTCR-seq,​ single-cell​ T cell receptor sequencing; TFH cell, T follicular helper cell; TH1 cell, T helper 1 cell; TIM3, T cell immunoglobulin and mucin domain-containing​ protein 3; TNF, tumour necrosis factor. severe COVID-19 (Fig. 1a). For example, observed in many, but not all, patients4,8,11,26. responses5,16, and recent scRNA-seq​ data there is evidence of terminally differentiated In other settings, CD38+HLA-DR​ + or Ki67+ from the upper respiratory tract imply that T cells or possibly exhausted T cells in CD8+ T cells that are present in the blood interactions occur there between epithelial severe disease, with reported increases in during the acute phase of a viral infection cells and cytotoxic T lymphocytes, in expression levels of the inhibitory receptors or after live-attenuated​ vaccination contain particular through an interferon-γ​ (IFNγ) PD1, TIM3, LAG3, CTLA4, NKG2A and virus-specific​ T cells27, which indicates that axis9. Indeed, more robust clonal expansion CD39 (refs4,8,10,11,23,24). However, expression there might be virus-specific​ CD8+ T cell of CD8+ T cells in peripheral blood28 or of these receptors could also reflect recent responses in those patients with COVID-19 bronchoalveolar lavage fluid5 may be activation, and it is not clear whether the who have robust CD38+HLA-DR​ + or Ki67+ associated with milder disease or recovery, T cells in patients with COVID-19 are CD8+ T cell responses. However, not all although it is not clear whether this CD8+ exhausted or just highly activated. By patients have this T cell activation phenotype T cell clonal expansion is the cause or contrast, at least one blood scRNA-seq​ study and current data point to potentially diverse consequence of the disease recovery. Last, has reported limited expression of inhibitory patterns of CD8+ T cell responses in patients there is evidence of SARS-CoV-2-​ ​specific receptors by CD8+ T cells in patients with COVID-19 (ref.8). CD8+ T cells in patients who have recovered, with COVID-19 compared with healthy Several important considerations arise which provides evidence not only of controls7. In one report, CD8+ T cells from from these studies: how does heterogeneity virus-specific​ CD8+ T cell responses but patients with severe COVID-19 had reduced of the CD8+ T cell response relate to disease; also of CD8+ T cell memory in many cytokine production upon stimulation23. how do T cell responses in peripheral blood convalescent patients29–32. The precise role of Alternatively, other data suggest that reflect events in the respiratory tract; and are these virus-specific​ CD8+ T cells in control CD8+ T cells might have a hyperactivation the CD8+ T cell responses antigen specific? of initial acute SARS-CoV-2​ infection signature, including high levels of First, multiple studies have indicated and their capacity to protect from future expression of natural killer cell-related​ heterogeneity in immune responses to infection remain to be determined. markers and increased cytotoxicity4,23,25. SARS-​CoV-2, including in CD8+ T cells, Some of these studies imply the presence and emerging data identify potentially CD4+ T cell responses in COVID-19 of an overaggressive CD8+ T cell response distinct patient immunotypes6,8 that might, Similar to CD8+ T cells, there is evidence or a hyperactive state in patients with in some cases, be related to disease features. of functional impairment and increased COVID-19 (ref.25). Increased numbers of Second, autopsy studies and scRNA-seq​ data expression of activation and/or exhaustion CD38+HLA-DR​ + activated CD8+ T cells or from bronchoalveolar lavage fluid suggest markers by CD4+ T cells in patients with Ki67+ proliferating CD8+ T cells were also the importance of respiratory CD8+ T cell COVID-19 (refs10,14) (Fig. 1b). Case reports

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a Proposed CD8+ T cell response during COVID-19

Cytokines, Activated chemokines T cells Cell TCR Cell cycle and Co-inhibitory Mild number clonality state cytotoxicity signals disease Effector T cells and terminally ++ IL-2, type I IFNγ +/– differentiated T cells + PD1 and type III Dominant IL-2 +/– Normal or +/– ++ TIM3 interferon clones Ki67 CD107a + increased + CD38 Clonal detected TNF +/– + CD39 expansion GZMB Memory T cells

++ Naive + PD1 IL-6, IL-10, Less activated IFNγ ++ T cell +/– TIM3 IL-1β, CXCL8 T cells? IL-2 CD38++ CD107a+ and other Terminally Exhausted- Lack of CD39+ Strongly GZMB++ CXCLs, TNF dominant +/+ NKG2A+ differentiated like T cell decreased Ki67 ++ clones Perforin KLRs+ Severe T cell + CCL3 LAG3+ disease ++ CCL4 CTLA4+ Memory + Reduced IL-1β TIGIT+ T cell pool? ? T cell

b Proposed CD4+ T cell response during COVID-19 Proliferating Co-stimulatory Cell Humoral and TH cells Mild Cell Lineage cycle immune co-inhibitory disease Systemic number specificity state memory signals IL-2, antiviral response CD38+/– +/– type I and TH1 cell, ICOS CD95– type III Germinal-centre Normal or TH2 cell, +/– CX3CR1+/– interferon B cell activation increased germinal- Ki67 Efficient centre PD1+/– Germinal- +/– TFH cell TIM3 +/– centre TFH cell CD39

Naive Plasmablast T cell hyperactivation + + ? IL-6, IL-10, ICOS CD38 ++ Circulating CD38 IL-1β, CXCL8 circulating TFH cells ICOS++ and other TFH cell, + Systemic Immune T 17 cell, CD95 CXCLs, TNF H +/+ + antiviral response cell subtype hyper-T 1 Ki67 Unknown CX3CR1 dependent H PD1+ Severe cell (Treg + cell?) TIM3 disease Hyperactivated CD39+ + TH1 cells TIGIT ? Immunopathology

+ CCR6 TH17 cell

Fig. 1 | Potential model of T cell responses during COVID-19 progres- CX3CR1, CX3C-​chemokine receptor 1; CXCL, CXC-​chemokine ligand; sion. A proposed model of CD8 + T cell responses (a) and CD4+ T cell GZMB, granzyme B; ICOS, inducible co-stimulator;​ IFNγ, interferon-γ​ ; KLR, responses (b) during COVID-19 progression in mild versus severe disease. killer cell lectin-​like receptor; LAG3, lymphocyte activation gene 3; TCR,

Tables show the immune parameters that have been reported to differ T cell receptor; TFH cell, T follicular helper cell; TH1 cell, T helper 1 cell; TH2 between mild and severe COVID-19. Phenotype data are collated from the cell, T helper 2 cell; TH17 cell, T helper 17 cell; TIGIT, T cell immunoreceptor references cited in this Progress article. Results that have been confirmed with immunoglobulin and ITIM domains; TIM3, T cell immunoglobulin and by multiple studies are indicated in bold type. CCL, CC-chemokine​ ligand; mucin domain-containing​ protein 3; TNF, tumour necrosis factor; Treg cell, CCR6, CC-chemokine​ receptor 6; CTLA4, cytotoxic T lymphocyte antigen 4; regulatory T cell. have suggested that CD8+ T cell activation SARS-​CoV-2 spike protein have been indicates a potential role for T helper 17 + might be greater than CD4 T cell activation, identified in acute infection and have a (TH17) cell-mediated​ immunopathology,­ 35 as defined by activation markers such as TH1 cell cytokine profile . A role for T whereas another study identified possible 26,33,34 + CD38 and HLA-DR​ . However, another helper 2 (TH2) cell-​type responses in severe increases in the number of CD4 T cells study identified a subset of patients with COVID-19 is unclear, although patients producing transforming growth factor-β​ + 36 + higher levels of CD4 T cell activation with mild disease may have a normal TH2 (TGFβ) . A population of CD4 T cells who possibly do worse clinically8. One cell response11. Given the prominent role of producing granulocyte–macrophage report has described a higher proportion TH2 cell responses in other lung diseases, colony-stimulating​ factor (GM-CSF)​ or of IFNγ-​producing T helper 1 (TH1)-like​ this is an important area for further study. IL-6 has also been reported in patients with cells in patients with moderate disease Two individual reports have also described COVID-19 (ref.37), although T cells do not than in patients with severe disease13. a strong CCR6+CD4+ T cell signature typically produce IL-6. Regulatory T cells36 Moreover, CD4+ T cells specific for the in severe COVID-19 (refs2,34), which and ICOS+CD38+ circulating T follicular

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8 helper (activated cTFH) cells may also be consistent with a recent observation of may also paradoxically be pro-inflammatory​ altered in patients with COVID-19, with reduced numbers of plasmacytoid dendritic and therefore perhaps contribute to 11 increased numbers of activated cTFH cells cells . This observation, however, contrasts immunopathology. Older patients in some settings perhaps connected to with the robust and consistent upregulation experience more severe lymphopenia during a reported increase in the number of of the interferon-inducible​ chemokine COVID-19 (ref.10), although it is not clear circulating plasmablasts4. CXCL10 observed in one patient cohort11, whether ageing-associated​ lymphopenia is Lymphopenia also affects CD4+ T cells, perhaps owing to non-interferon​ inducers causal to disease severity or vice versa. although some studies suggest that the of expression of this chemokine. Men with COVID-19 have higher impact is less than that for CD8+ T cells8,38. Another key gap in our understanding is rates of hospitalization and mortality than It remains to be determined how the relationship between viral load and the women58, and among severe cases of disease, lym­phopenia might relate to CD4+ T cell immune response. Viral load could have a men have more severe lymphopenia59. activation and/or dysfunction. Moreover, in major impact on the magnitude and quality There may also be a bias to stronger CD4+ addition to memory CD8+ T cells, patients of the T cell response, and future studies that and CD8+ T cell activation in women with who have recovered from SARS-CoV-2​ quantify virus replication should provide COVID-19 (ref.60). It is unclear whether these infection have virus-specific​ memory context for understanding evolving T cell sex biases relate to X chromosome-encoded​ CD4+ T cells29–32, which bodes well for the responses during SARS-CoV-2​ infection. immune genes58 and/or the role of sex possibility of T cell memory and, perhaps, A key feature of patients with COVID-19 hormones in regulating immune responses61. protective immunity. In individuals is the enrichment for co-morbidities​ such Nevertheless, these data highlight the who recovered from mild COVID-19, as hypertension and diabetes42 (see next importance of accounting for sex in ongoing CD4+ T cells gained a typical memory section), but it remains to be defined clinical trials. phenotype with high levels of expression of how an individual patient’s background A very high proportion of patients IL-7Rα (ref.32). Interestingly, cross-reactive​ ‘immune health’ landscape shapes responses with COVID-19 who are hospitalized have memory CD4+ T cells are also found in to SARS-​CoV-2 infection. Although one or more underlying cardiovascular subjects who have never been exposed to lymphopenia is not a unique feature of co-morbidities​ 44,45,62–64. Moreover, many SARS-CoV-2​ (ref.29). It is unclear how these SARS-CoV-2​ infection43, it may be more of the manifestations of severe disease pre-​existing memory CD4+ T cells, which prolonged in patients with COVID-19, relate to coagulopathies and vascular are presumably generated in response and lymphopenia-​induced proliferation complications62,64. Even the newly recognized to human endemic coronaviruses, affect can clearly affect T cell differentiation and SARS-CoV-2-​ associated​ multisystem immunity or pathology upon SARS-CoV-2​ activation; however, the contribution of inflammatory syndrome in children has infection. There are other settings in which lymphopenia to T cell differentiation in similarities to Kawasaki disease, which the presence of memory CD4+ T cells patients with COVID-19 has not yet been often involves inflammation of the coronary in the absence of effective CD8+ T cells or investigated. artery65,66. Other viral infections, including antibodies can cause pathology39. Thus, Ebola virus and virulent lymphocytic CD4+ T cell responses are present in patients Co-morbidities​ and COVID-19 choriomeningitis virus in mice, can cause with COVID-19 and perhaps form memory Co-​morbidities such as cardiovascular damage to the vascular endothelium. These following resolution of the disease. Whether disease44,45, diabetes42 and obesity46 are viruses infect the vascular endothelium, CD4+ T cells responding in acute infection some of the most common underlying and T cells can then cause vascular damage with SARS-​CoV-2 are functionally impaired conditions associated with worse clinical by attacking the virus-infected​ cells67–69. or hyperactivated, and how these responses outcome and severe COVID-19. Moreover, However, disease presentation in these relate to disease outcome, remain important older patients experience greater clinical settings is distinct from that for COVID-19, unanswered questions. severity of COVID-19 (refs1,47), males and extensive SARS-CoV-2​ infection of may experience more severe disease than the vascular endothelium is unlikely in T cell differentiation in COVID-19 females1,47 and genetic variations, including most patients. Most acute viral infections in humans the ABO blood type8,48,49, have been reported Obesity also contributes to more induce the activation and proliferation to affect the clinical outcomes for patients severe COVID-19 and higher rates of of both CD4+ T cells and CD8+ T cells, with COVID-19. However, how these hospitalization46,70, which are perhaps so SARS-​CoV-2 infection may not be unique co-​morbidities are associated with T cell associated with the role of body mass index in this regard. However, hyperactivation responses during COVID-19 remains in cardiovascular health. However, obesity or hypoactivation of T cells, or skewing largely unknown. can also directly affect T cell responses towards an ineffective differentiation state Advanced age is a common co-morbidity​ to influenza vaccination71 or infection72,

(for example, TH17 cells, exhausted T cells or for severity of disease during respiratory and a role for obesity in altering T cell terminally differentiated T cells), might not viral infections, and disease severity differentiation has been observed in asthma73 be optimal in some patients with COVID-19. may be associated with altered T cell and chronic inflammation74. Nevertheless, Several features that have been described responses50,51. Ageing affects T cell repertoire the precise role of T cells in driving the in patients with severe COVID-19 — diversity52, both for CD4+ T cells53 and for coagulopathies or inflammation that are including high levels of systemic cytokines CD8+ T cells54. This age-related​ reduction characteristic of severe COVID-19 in or chemokines, most notably IL-6, CXCL8, in T cell clonal diversity is associated with patients with cardiovascular co-morbidities​ CXCL9 and CXCL10 (refs8,11,40), or delayed impaired responses to viral infections such is unclear. or defective type I interferon responses41 — as influenza55. Advanced age can also be Finally, a recent genetic association study could potentially skew T cell responses. associated with T cell senescence, which compared patients with severe COVID-19 The potential type I interferon deficiency perhaps contributes to ineffective responses and ARDS with healthy controls49. Several described in patients with COVID-19 is to infections56,57. However, senescent T cells chemokine receptor genes, including CCR9,

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CXCR6 and XCR1, and the locus controlling different stages of disease or with different be important. Although evidence of the ABO blood type were identified as being immune response characteristics and then T cell memory to other coronaviruses is associated with severe disease. Whether to match them with treatment strategies. encouraging, such immune natural history these genes are directly or indirectly related Such a precision medicine strategy studies for SARS-CoV-2​ will likely be to T cell responses in COVID-19, however, based on analysis of ‘immune health’ valuable for examining vaccine-induced​ remains unknown and needs further could be used to better tailor the use of T cell responses. investigation. immunostimulatory strategies such as Thus, although severe COVID-19 is thymosin α1 (ref.25) or type I interferon75 Conclusions partially characterized by patients with versus immunosuppressive drugs such The accumulating evidence supports a role co-​morbidities, how these co-morbidities​ as tocilizumab76–78, ruxolitinib79 or for T cells in COVID-19 and probably in relate to T cell responses remains poorly dexamethasone80 to patients who will receive the immunological memory that forms understood. Causal associations may most benefit. These efforts should be aided following recovery from SARS-CoV-2​ exist, perhaps connected to some of the by the development of better preclinical infection. Most, although not all, patients underlying genetics. However, it is also models, including human ACE2-expressing​ who are hospitalized seem to mount both possible that certain co-morbidities​ mice81–85. It will be interesting in the future CD8+ and CD4+ T cell responses, and or pre-​existing conditions make to use such models to address key questions evidence points to possible suboptimal, patients with severe disease less able to including: what is an ‘appropriate’ profile excessive or otherwise inappropriate T cell tolerate the severe virus-mediated​ and of T cell activation and differentiation for a responses associated with severe disease. immune-​mediated pathology associated successful antiviral response to SARS-CoV-2​ In fact, multiple distinct patterns of T cell with SARS-CoV-2 infection.​ without triggering severe pathology; response may exist in different patients, how does viral load or initial inoculum of which suggests the possibility of distinct Strength of COVID-19 T cell response SARS-​CoV-2 impact T cell responses and clinical approaches tailored to the particular The published data discussed here indicate pathology; how do T cell responses in the immunotype of a specific patient. Much that patients with severe COVID-19 can blood relate to lung-infiltrating​ T cells, of the available data on T cell responses have either insufficient or excessive T cell considering that many respiratory viruses in patients with COVID-19 who are responses. It is possible, therefore, that are controlled by tissue-resident​ immune hospitalized is still available only in preprint disease might occur in different patients cells that may not be present in the blood; form. This format has been essential for at either end of this immune response and what are the molecular mechanisms rapid dissemination of information in the spectrum, in one case from virus-mediated​ that support a successful T cell response setting of pandemic urgency. However, pathology and in the other case from during SARS-​CoV-2 infection? as these studies move through peer review, T cell-​driven immunopathology4. However, we should gain increasing confidence and it is unclear why some patients respond T cell memory in COVID-19 clarity about the nature of T cell responses too little and some patients too much, and A key question is whether protective to SARS-​CoV-2 infection. More carefully whether the strength of the T cell response T cell memory can form following either defining distinct classes of T cell response in the peripheral blood reflects the T cell SARS-CoV-2​ infection or vaccination. types in COVID-19 and delineating how response intensity in the respiratory tract and Although data on vaccination will await pre-existing​ conditions, co-morbidities,​ other SARS-CoV-2-​ infected​ organs. Some trial results, early data from patients race, ‘immune health’ status and other information exists on SARS-CoV-2-​ specific​ with COVID-19 who have recovered are variables influence T cell responses should T cells in patients who are hospitalized, and promising. Memory CD4+ T cells and reveal novel opportunities for treatment approaches using activation markers (such CD8+ T cells were detected in 100% and prevention. as Ki67) likely capture virus-specific​ T cell and 70% of patients who recovered, Zeyu Chen and E. John Wherry ✉ 29 responses; recent studies are beginning to fill respectively . Moreover, memory T cell Department of Systems Pharmacology and in this picture by identifying virus-specific​ responses were detected for multiple Translational Therapeutics, Institute for Immunology, CD4+ T cells and CD8+ T cells in acute SARS-CoV-2​ proteins, including not only Perelman School of Medicine, University of disease5,29,30. However, one missing set of spike protein but also nucleoprotein and Pennsylvania, Philadelphia, PA, USA. information is a careful immune analysis membrane protein31. Whether these T cells ✉e-mail:​ [email protected] of outpatients who, during acute infection provide protective immunity is unclear, https://doi.org/10.1038/s41577-020-0402-6 with SARS-​CoV-2, are undergoing a and addressing this question for T cells Published online 29 July 2020 ‘successful’ immune response. Moreover, alone will be confounded by the presence of 1. Huang, C. et al. Clinical features of patients infected it will be crucial to incorporate into any SARS-CoV-2-​ ​specific antibodies in patients with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020). model of COVID-19 how the magnitude and who recover. Nevertheless, ongoing analysis 2. Xu, Z. et al. Pathological findings of COVID-19 quality of T cell responses relate to signals of patients who have recovered should associated with acute respiratory distress syndrome. Lancet Resp. Med. 8, 420–422 (2020). from other parts of the immune system, such provide insights into the protective capacity 3. Matthay, M. 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Preprint at bioRxiv https://doi.org/10.1101/2020. Acknowledgements Peer review information 05.27.118893 (2020). Z.C. is supported by grant CA234842 from the National Nature Reviews Immunology thanks Susan L. Swain and the 82. Sun, J. et al. Generation of a broadly useful model for Institutes of Health (NIH). Work in the Wherry laboratory other, anonymous, reviewer(s) for their contribution to COVID-19 pathogenesis, vaccination, and treatment. is supported by NIH grant AI082630, the Allen Institute the peer review of this work. Cell https://doi.org/10.1016/j.cell.2020.06.010 for Immunology and the Parker Institute for Cancer (2020). Immunotherapy. Publisher’s note 83. Hassan, A. O. et al. A SARS-​CoV-2 infection model Springer Nature remains neutral with regard to jurisdictional in mice demonstrates protection by neutralizing Author contributions claims in published maps and institutional affiliations. antibodies. Cell https://doi.org/10.1016/ The authors contributed equally to all aspects of the article. j.cell.2020.06.011 (2020). 84. Bao, L. et al. The pathogenicity of SARS-​CoV-2 Competing interests Related links in hACE2 transgenic mice. Nature https://doi.org/ E.J.W. has consulting agreements with and/or is a scientific CoVID-19 Map of the Johns Hopkins Coronavirus resource 10.1038/s41586-020-2312-y (2020). advisor for Merck, Roche, Pieris, Elstar and Surface Oncology. Center: https://coronavirus.jhu.edu/map.html 85. Jiang, R.-D. et al. Pathogenesis of SARS-​CoV-2 in E.J.W. has a patent licensing agreement on the PD1 pathway transgenic mice expressing human angiotensin-​ with Roche/Genentech. E.J.W. is a founder of Arsenal converting enzyme 2. Cell 182, 50–58 (2020). Biosciences. Z.C. declares no competing interests. © Springer Nature Limited 2020

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