key: cord-0986756-87jptt6o authors: Hanna, Stephanie J; Codd, Amy S; Gea-Mallorqui, Ester; Scourfield, D Oliver; Richter, Felix C; Ladell, Kristin; Borsa, Mariana; Compeer, Ewoud B; Moon, Owen R; Galloway, Sarah A E; Dimonte, Sandra; Capitani, Lorenzo; Shepherd, Freya R; Wilson, Joseph D; Uhl, Lion F K; Gallimore, Awen M; Milicic, Anita title: T cell phenotypes in COVID-19 date: 2020-12-29 journal: Oxf Open Immunol DOI: 10.1093/oxfimm/iqaa007 sha: 35ab5a78db6bd878692635ca88eb6cdb7f8bc546 doc_id: 986756 cord_uid: 87jptt6o COVID-19 is characterised by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterised by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2 specific T cells to elucidate markers which may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that whilst some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation. The T cell arm of the adaptive immune system is vital in the host defence against viral pathogens and in long-lasting immune memory that prevents re-infection. Therefore, an understanding of T cell phenotypes and functions is crucial to enable better treatment of COVID-19, caused by the novel virus SARS-CoV-2. SARS-CoV-2 belongs to the coronavirus family which includes SARS-CoV-1, MERS-CoV and "common cold" coronaviruses (OC43, HKU1, 229E and NL63) [1] . SARS-CoV-1 and MERS-CoV both cause severe disease with high fatality rates. SARS-CoV-1 infection is characterised by lymphopenia and reduced activation of T cells [2] , whilst in MERS-CoV infection lymphopenia is less prevalent, T cells can be directly infected by MERS-CoV and mount a Th17-driven response [3] . In both cases, long-lived memory T cells are generated [4, 5] . The T cell response to SARS-CoV-2 is strikingly different to that which occurs in response to influenza [6, 7] . Direct comparisons between patients with influenza and COVID-19 (including patients from both groups with acute respiratory failure) demonstrate that those with influenza had increased IFN pathway responses and reduced TNF and IL-1β responses compared to patients with COVID-19 [6, 7] . COVID-19 is characterised by lymphopenia [8] and T cell phenotypes are drastically altered. Furthermore, it is becoming clear that these phenotypic changes may be important in determining the course of disease [9] . A pattern is emerging of heterogeneous T cell phenotypes which display elements of activation and proliferation but also exhaustion and lack of cytokine production. This review examines this heterogeneity and how it correlates with disease severity. SARS-CoV-2-specific T cell phenotypes and T cell phenotypes in the lung and in recovery are also discussed, along with indications of T cell memory formation. Most studies have examined the phenotype of all T cells in the peripheral blood of COVID-19 patients, however, some studies have used tetramers or in vitro activation assays to identify and characterise SARS-CoV-2 specific T cells. Section 1 of this review will examine the gross phenotypic changes seen across T cells as a whole in the peripheral blood (of which the majority will not be specific for SARS-CoV-2), whilst section 2 will focus upon SARS-CoV-2 antigen-specific T cells. In COVID-19 there is a striking loss of T cells, particularly of naïve CD4+ T cells [10] , [11] , but many effector and memory subsets are proportionally increased (although due to lymphopenia this may still represent a reduction in absolute numbers). Changes in specific subsets, and correlation with disease severity are summarised in Table 1 . It is not clear whether naïve cells are converting to an effector/memory phenotype or lost from the periphery altogether. Most likely, given the substantial reductions in T cell counts, both mechanisms occur. Numbers of proliferating T cells have been reported to increase in most COVID-19 patients [12, 13] , although up to a third of patients have no increase in the percentage of KI-67+ cells compared to healthy donors [10] . Many T cells subsets proliferate during COVID-19, including those that are usually quiescent, such as TCM (central memory) and TEM (effector memory) subsets [10] with 10-fold increases in the percentage of blood CD4+ and CD8+ TEM cells in G1 or S-G2/M cell cycle phases [14] . Furthermore, subsets may be proliferating even though they are decreased in frequency [10] . Proliferation rate is likely influenced by disease stage and severity and enhanced in severe disease [15] . Proliferation of CD4+ T cells also correlates with anti-SARS-CoV-2 IgG [14] . 1.3 T cell phenotypic markers and cytokine production: activation and exhaustion CD8 + T cells in COVID-19 patients have phenotypes associated with activation, cytotoxicity and cytokine production [13] ( Figure 1A ). There is an increased frequency of activated HLA-DR + CD38 + T cells [10, [14] [15] [16] , particularly among memory T cells and CD8 + T cells in patients who later progress to severe disease [8, 14, 15] . Over the course of active infection there is a decline in activated CD8 + CD38 + HLA-DR + T cells [17] . Non-naïve CD8+ T cells are enriched for expression of CD39, CD27, PD1, ICOS and CD95 (FAS). [10] CD4 + and CD8 + T cells in infected patients express high levels of activation markers such as CD25 [18] and CD69 [19] (although whether this increases [20] or decreases [21] over time is unresolved) and effector markers such as NKG7 [13] , whilst overexpression of HIF-1 ( Hypoxia-inducible factor-1) in T cells suggests an adaptation to hypoxic conditions [14] . CD4 + TCM cells have increased expression of activation markers including PD-1 (used as both a marker of activation and exhaustion), CD95, and ICOS [10] . TEM and circulating T follicular helper cells (cTfh) show high levels of proliferation and HLA-DR/CD38 co-expression [10] . A good prognosis is indicated by higher levels of CXCR3 + CD4 + T cells [22] and high expression of CD69 [21] at the time of hospital admission. The most severe disease is associated with decreased frequencies of CD11a + T cells and CD28 + CD4 + T cells [23] and increased HLA-DR + CD57 + T cells [23] . Most, but not all [12] , studies have also reported an exhausted [24] or senescent [25] T cell phenotype, particularly in CD8 + T cells [24] , and link disease severity with decreased polyfunctionality and cytotoxicity [24, 26, 27] . Exhaustion markers increase as disease progresses [26] and high levels of exhaustion markers correlate with a poor prognosis at the time of hospital admission [24] . PD-1 [14, 18, 26] , Tim-3 [26, 28] , CTLA4 [14, 29] , LAG3 [14] , BTLA (B and T lymphocyte attenuator) [30] and the inhibitory receptor NKG2A [27] have been identified as markers of chronic activation, inhibition and an exhaustion in both CD4 + and CD8 + T cells. CD4 + T cells upregulate PD-1 in all subsets except naïve populations [10, 15, 19, 30] and this is more pronounced in severe disease [15] . CD73 is also downregulated [30] , again suggesting exhaustion. Overexpression of TRAIL-receptor and CASP3 suggested that CD8+ TEM were more prone to apoptosis [14] . There are conflicting reports of TIGIT expression being down regulated [14] , or increased [30] in T cells. It has also been suggested that TIGIT's ligand PVR may directly interact with SARS-CoV-2 [14] . Polyfunctionality in viral infections is often related to a better immune control of the infection [31] . In COVID-19 the loss of cytokine production (IL-2, IFNγ or TNFα) [24] and antiviral activity (CD107a and Granzyme B) [27] in both CD4 + and CD8 + T cells may be an important contributing factor to disease severity [12, 25] . Elderly (> 80 years old) patients in particular had an impaired CD8+ T cell cytotoxic response [32] . However, some reports found that T cells in COVID-19 patients, including those with severe disease, expressed substantial amounts of IFNγ [9, 33] , IL-17 [9] , FASLG, Granzyme A and perforin [14] . In addition, CD8+ TEF expressed PTGDR, a mediator of airway inflammation, Granzyme K and XCL2 [33] , whilst TEMRA-like populations expressed CX3CR1, T-bet, and Granzyme B [10] . Therefore, an alternative possibility is that these functional responses exacerbate COVID-19 disease. Little is known about asymptomatic disease, but one study suggests that these individuals have increased IFNγ, XCL2 and CD69 expression on T cells, and expansion of a Th2-like subset expressing TNFRSF19 (Tumor necrosis factor receptor superfamily, member 19) [34] . A picture emerges of initial T cell activation in response to infection and cytokine-driven bystander activation -indeed, many phenotypic changes correlate with levels of IL-6 or CXCL10 in the serum [14] . T cell activation then progresses to exhaustion, although it is clear that many individual cells simultaneously express markers of both activation and exhaustion [14] . This occurs in the context of viral evasion [35] and impaired innate responses including IFN type I production [36] , which results in reduced virus clearance. It has been proposed that the higher viral titre (due to the reduced viral clearance) leads to further T cell priming [37] . In mild disease appropriate activation is followed by exhaustion whereas in severe disease excessive activation may be followed by more profound exhaustion. Innate and γδ T cells are activated and expanded by nonpeptidic antigens and aid elimination of viral and bacterial infections [38] . In COVID-19, circulating and lung innate NKT (Natural of both CD69 and PD-1 with reduced secretion of IFN-γ, suggesting that they are both activated and exhausted [21] . MAIT cell CD69 high , PD-1 high and CXCR3 low phenotypes associated with poor outcome [39] . In addition, MAIT cells show increased CD56 expression and Granzyme B production [40] . A reduction in the proportion of CD8 + MAIT cells [15] and γδ T cells has been observed in the peripheral blood, with Vγ9Vδ2 cells nearly completely absent [14, 41] , particularly in patients with severe disease. The remaining γδ T cells are predominantly Vδ1 + and highly proliferative, with over 10-fold increases in the proportion of γδ T cells in early cell cycle and G1 [14] , whilst many of the remaining Vγ9Vδ2 cells transition to a memory phenotype over the course of infection [41] . γδ T cells in COVID-19 also express high levels of CD25 [42] . NKT-like cells have increased production of Granzyme B and perforin and their numbers are similar to healthy controls in mild disease, expanded in moderate COVID-19 [43] , and decreased in severe disease [44] . After SARS-CoV-2 has been cleared from the body, T cell counts seem to recover to near normal levels for most patients, although the trajectory of this recovery is associated with the extent of depletion [10, 15, 45, 46] . Abnormalities in T cell phenotypes also persist after the resolution of infection ( Figure 1B) . During recovery, effector T cells convert to several different memory subsets [23, 44] , with a prolonged conversion to TCM [33] and a stem-like memory phenotype [19] . In addition, during early stages of recovery, CD4 + T cells express genes associated with positive regulation of cell killing [33] whilst at later stages they express genes associated with migration and adhesion [33] . Th2-like ICOS + Tfh cells are enriched in recovering patients [33] and activated circulating Tfh (cTfh) frequencies are higher in recovered patients than healthy donors [10] , indicating support for B cell antibody production (although there are reports of reduced Tfh in recovered patients [45] or at the level of healthy controls [15] . However, there are indications that T cell effector functions may remain impaired in recovered patients. More than a month after hospital discharge, recovered patients had higher levels of CD8 + TEF and TEM, increased levels of IL-7R on naïve CD8 + T cells compared to healthy controls [33] , reduced production of IFNγ, IL-4, IL-17 and Granzyme B by both CD4 + and CD8 + T cells, and increased Treg frequencies compared to uninfected individuals [45] . There are conflicting reports of PD-1 expression in recovered patients being similar to healthy controls [29, 45] or remaining elevated [10] , whilst TIM3 expression on T cells remains high [45] . MAIT cell lev els normalised in the convalescent phase [39] , whilst NKT cell numbers remained low two months after infection had resolved [45] . It is possible that these T cell perturbations may recover over a longer period than is currently available to assess. However, if persistent, these phenotypes could bring an increased susceptibility to infections and autoimmune diseases. Antigen-specific CD8+ T cells, particularly in the early stages of infection, express CD38, HLA-DR, KI-67 and PD-1 [19] (Figure 1C ). They also have effector functions, expressing IFNγ, CD107a, FasL, CCL3, CCL4, Granzyme B [47] and TNF [19] , although T cells from patients with severe disease are less likely to be polyfunctional [29] . Expression of many of these, along with clonal expansion, is associated with severe disease [48] . SARS-CoV-2-specific CD4 + T cells predominantly had a central memory (CD45RA -CCR7 + ) phenotype [20] , with spike glycoprotein (S) reactive CD4+ T cells displaying an activated/proliferating phenotype (CD38+ HLA-DR+ KI-67+ PD-1+) [19] . SARS-CoV-2-specific T cells from recovered patients were able to express IL-2, IFNγ, TNFα [4, 19, 29] and Granzyme B [47] . Intriguingly, T cells with different SARS-CoV-2 epitope specificities have different phenotypes, with spike-specific CD4 + T cells skewed towards cTfh, whereas membrane (M) protein -specific and nucleocapsid (N) specific CD4 + T cells were predominantly Th1/Th17 [19] . Similarly, M/NP-specific CD8 + T cells showed wider functionality than T cells targeting the Spike protein [49] . SARS-CoV-2-specific CD8 + T cells include large proportions of both central memory (CD45RA -CCR7 + ) and terminally differentiated cells (CD45RA + CCR7 -) [20] . In recovered patients, SARS-CoV-2 -specific CD4+ cells also have a TCM/Th1 phenotype with high levels of CXCR5, ICOS and CD127 [50] and higher levels of CTLA4 than patients with active disease [47] . During recovery, CD8+ T cells have an early stem cell memory phenotype (CCR7+ CD127+ CD45RA+ TCF-1+) [19] . Others have described the SARS-CoV-2 -specific CD8+ T cells in recovery as atypical CD27+CD28+ TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) [50] , TCM or TEM [49] . Another study found that CD95+ CD45RA+ TEMRA, CCR7+ CD45RO+ CD27+ CD28+ CD95+ TCM and CD45RO+ CD95+ TEM SARS-CoV-2specific CD8+ T cells corresponded to "high prevalence" peptide responses, which were detected in >35% of donors of each allele group [51] . Comparatively, 'low prevalence' responses i.e. those occurring in fewer individuals, comprised mainly CCR7+ CD45RO+ CD27+ CD28+ CD95+ TCM and CCR7+CD27+ CD28+ CD95+ CD45RA+ TSCM (central memory and stem cell memory, respectively) cells [51] . The high prevalence were also more differentiated (CD57+ and CD161+) compared to the low prevalence (CCR7+ CD28+ CCR7+) SARS-CoV-2specific CD8+ T cells [51] . Spike-specific cTfh cells were abundant in recovered patients, (indicating support for B cell responses and antibody production), biased towards cTfh17 (CCR6 + CXCR3 − ), and correlated with neutralising antibody titres [52] . It is suggested that people with asymptomatic COVID-19 may have expansions of SARS-CoV-2-specific CD4+, but not CD8+ T cells [34] . Reassuringly, functional, antigen-specific T cells were found in people who had recovered from asymptomatic COVID-19 [19] . Another study of recovered patients found broad SARS-CoV-2-specific CD4+ and CD8+ T cell responses, with strength and breadth of target peptides correlated to disease severity [49] . In addition, T cell responses correlated with antibody titres [49] . Many reports have found that previous common cold coronavirus infections result in the generation of memory T cells that can cross-react with SARS-CoV-2 [4, 19, 48, [53] [54] [55] [56] . Furthermore, in a case study of the T cell repertoire of one donor characterised both prior to and in recovery from COVID-19 infection, it was found that pre-existing TCM cells had TCRs that recognised SARS-CoV-2 epitopes. However, after SARS-CoV-2 infection, these SARS-CoV-2 reactive TCRs were now found in the TEM population, with a small fraction in the TSCM [57] . Overall, SARS-CoV-2 specific cells appear to retain a more activated and less exhausted profile [48, 58] . In the airways of moderately severe COVID-19 patients, CD8 + T cells display an anti-viral phenotype, with high expression of CCL5 and cytotoxic receptors [58] (Figure 1D ). In severe COVID-19, CD8 + T cells in the airways show increased proliferation but are decreased in number overall [59] , implying that peripheral lymphopenia is not solely due to recruitment of T cells to the lungs. T cells from bronchoalveolar lavage (BAL) of patients with mild disease are differentiated and express Granzyme A, Granzyme K, FASLG and CCL5 as well as XCL1, XCL2 [59] , whereas T cells from patients with severe disease appear exhausted, lack Th17 and resident memory markers and effector functions [60] . Tregs were increased in the pleural fluid of a COVID-19 patient, compared to the peripheral blood [61] . CD8+ T cells expressing CCL3, CCL4, CCL5 and CXCR4, and CD4+ T cells expressing CCR4, CD38, HLA-DR and PD-1 were enriched in the pleural fluid whilst both CD4+ and CD8+ T cells expressed LAG-3, TIM-3, and PRDM1, indicating exhaustion, and cytokine production was decreased [62] . MAIT cells are enriched in the lungs [39] . These findings highlight the aberrant responses of T cells in the lung, which appear similar to those in the peripheral blood, with over-activation and exhaustion, as a factor in severe disease. Many questions remain regarding the T cell phenotypes in SARS-CoV-2 infection, in particular as stratified by early/late stages and disease severity. Some patients manage to mount an effective anti-viral response, although most of the data show a dysregulated and inefficient response with T cell over-activation followed by exhaustion in both the periphery and the lungs. T cell profile at the point of hospital admission can give useful indication as to the disease prognosis and stratification of patients at this point could enable use of effective immuno-modulating drugs [11] . Evidence of T cell apoptosis is limited, and the causes of lymphopenia remain unknown. The available data are mostly from advanced infection in hospitalised patients and there is a need to characterise the T cell response in the early stages of severe disease, and over the whole time-course of mild and asymptomatic infections [63] and in children [64] . In other settings, such as the treatment of multiple sclerosis with alemtuzumab, rapid reduction in lymphocyte numbers is followed by uneven repopulation of T and B cell subsets, leading to a variety of autoimmune diseases due to a lack of T cell regulation of B cell responses [65] and the homeostatic expansion of autoreactive T cells [66] . Therefore COVID-19 recovery, where lymphocyte repopulation is accompanied by high levels of T cell activation and increased numbers of activated cTfh harbours a heightened risk of autoimmunity. It is already known that a variety of autoimmune conditions can be induced during COVID -19 infection [67] , and that rate of onset of type 1 diabetes appears increased following COVID-19 [68] . Future research will undoubtedly focus on characterising T cell functional deficits and consequences of a persistent phenotypic perturbation following COVID-19.  In parallel with overall T cell depletion COVID-19, T cell phenotypes including memory and effector subsets and cTfh are expanded and activated. The mechanisms for this, e.g. antigen specific responses, bystander activation in response to cytokine milieu, are not well explored. A. T cell phenotypes in the peripheral blood are characterised by a loss of naïve T cells and an increase in many memory T cell subsets. T cells are activated upon recognition of virus, or in response to cytokines for example IL-6 or IFNγ. Activation and antiviral activity is followed by exhaustion and reduction in cytokine production, although the balance between activation and exhaustion correlates with, and may contribute to, disease severity. Decreased effector functions (particularly in CD8+ T cells), and reduced cytokine production result in a reduced ability to clear virus from body. B. In recovery, whilst some phenotypic changes return to normal, others persist (over the timescale currently available to investigators). This includes a persistent elevation of Tfh cell, an increased percentage of TEM that over time are replaced by TCM or TEMRA, persistent exhaustion of effectors, and increased activation of naïve cells. C. SARS-CoV-2 specific T cells have a range of effector, memory and follicular helper phenotypes and display a range of activation markers and cytokine production, with relatively little evidence of exhaustion. In the recovery phase of COVID-19, these antigen-specific cells convert to long-lived TCM and TSCM phenotypes, with antigen-specific Tfh cells also persisting. D. In the lungs, the T cell response is dominated by clonal expansions of CD8+TRM (resident memory) cells, although in severe disease, CD4+ TEM and Tregs are also found. Exhaustion of CD8+ T cells in the lungs appears less pronounced than in the periphery. Refs Naïve T cells Decrease [10] Naïve CD4 + T cells More severe disease [22] Activated Tfh Increased More severe disease [15, 30] Th17 Increased [30] Non-conventional (CCR6 + CCR4 + CD161 + IL-1RI + ) Th1 (Th1 * ) Increased [30] Tregs Increased in some More severe disease [22, 30, 69] Activated CD4 TCM-like Increased [10] CD4 + TEMRA Increased Milder disease [10, 23, 44] TCM Milder disease [23] CD4 + memory cells Milder disease [22] Th2 More severe disease [8, 22] CD8 + TEMRA Increased Milder disease [10, 23] CD8 + CD27 -CCR7 + TEM Increased [10] CD8 + CD27 + CCR7 -TEM Decreased [10] CD4 + CD8 + double-positive T cells Increased [17] MAIT Decreased (in periphery) Milder disease [39] [40] SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview T cell-mediated immune response to respiratory coronaviruses Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Infection, Immunological Response, and Vaccine Development SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19 Targeted Immunosuppression Distinguishes COVID-19 from Influenza in Moderate and Severe Disease Early phases of COVID-19 are characterized by a reduction of lymphocyte populations and the presence of atypical monocytes Longitudinal analyses reveal immunological misfiring in severe COVID-19 Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications T cell responses in patients with COVID-19 A single-cell atlas of the peripheral immune response in patients with severe COVID-19 Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm A dynamic COVID-19 immune signature includes associations with poor prognosis Comprehensive mapping of immune perturbations associated with severe COVID-19 Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19 Immune responses and pathogenesis in persistently PCR-positive patients with SARS-CoV-2 infection Naturally activated adaptive immunity in COVID-19 patients Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19 Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients Dysregulation of the immune response affects the outcome of critical COVID-19 patients COVID-19 progression is potentially driven by T cell immunopathogenesis Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19) Functional exhaustion of antiviral lymphocytes in COVID-19 patients Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients High levels of SARS-CoV-2 specific Tcells with restricted functionality in severe course of COVID-19 Next-Generation Sequencing of T and B Cell Receptor Repertoires from COVID-19 Patients Showed Signatures Associated with Severity of Disease T-cell quality in memory and protection: implications for vaccine design Impaired Cytotoxic CD8+ T Cell Response in Elderly COVID-19 Patients Single-cell RNA-seq and V(D)J profiling of immune cells in COVID-19 patients Longitudinal Single-Cell Immune Profiling Revealed Distinct Innate Immune Response in Asymptomatic Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients Adaptive immunity to SARS-CoV-2 Protective Role of γδ T Cells in Different Pathogen Infections and Its Potential Clinical Application MAIT cell activation and dynamics associated with COVID-19 disease severity Outcome of SARS-CoV-2 Infection Linked to MAIT Cell Activation and Cytotoxicity: Evidence for an IL-18 Dependent Mechanism More bricks in the wall against SARS-CoV-2 infection: involvement of γ9δ2 T cells The phenotypic changes of γδ T cells in COVID-19 patients Defining the CD39/CD73 Axis in SARS-CoV-2 Infection: The CD73-Phenotype Identifies Polyfunctional Cytotoxic Lymphocytes Reappearance of effector T cells is associated with recovery from COVID-19 Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19 High Levels of SARS-CoV-2 Specific T-Cells with Restricted Functionality in Patients with Severe Course of COVID-19 Severely ill COVID-19 patients display augmented functional properties in SARS-CoV-2-reactive CD8+ T cells Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19 SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential CD8+ T cell responses in convalescent COVID-19 individuals target epitopes from the entire SARS-CoV-2 proteome and show kinetics of early differentiation Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19 Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19 SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition Longitudinal High-Throughput TCR Repertoire Profiling Reveals the Dynamics of T Cell Memory Formation after Mild COVID-19 Infection COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19 Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages Single-cell analysis reveals bronchoalveolar epithelial dysfunction in COVID-19 patients Single-Cell Analysis Reveals Macrophage-Driven T Cell Dysfunction in Severe Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections COVID-19 in children and altered inflammatory responses Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation Autoimmune and inflammatory diseases following COVID New-Onset Type 1 Diabetes in Children During COVID-19: Multicenter Regional Findings in the U.K. Diabetes Care Funders: GW4 BioMed MRC Doctoral Training Partnership: LC European Union's Horizon 2020 under the Marie Sklodowska-Curie grant agreement 893676: MB Tenovus Cancer Care Appendix 1: The Oxford-Cardiff COVID19 Literature Consortium -Extensive author list