Cellular immune response to SARS-CoV-2 infection according to disease phenotype
| Author | Study type | Patients N | Control N | Cells | RoB | |
| COVID-19 (mild, moderate and/or severe) vs healthy donors | ||||||
| Neutrophils | Schulte-Schrepping et al22 | CyTOF, single cell RNA seq, flow cytometry | 58 (40 COVID-19, 8 influenza) | 10 HD | ↑ LDN, FUT4(CD15)+ CD63+ CD66b+ pro-neutrophils, and ITGAM(CD11b)+ CD101+ pre-neutrophils, reminiscent of emergency myelopoiesis, ↑ CD274(PD-L1)+ ZC3H12A+ mature neutrophils reminiscent of gMDSC-like cells | Unclear |
| Silvin et al23 | CyTOF, single cell RNA seq | 13 COVID-19 (mild 5, severe 8) | 25 HD | ↑ neutrophils ↑ CD10LowCD101+ neutrophils in patients with mild disease, whereas ↑ CD10LowCD101− neutrophils in patients with severe disease | Unclear | |
| Monocytes | Arunachalam et al27 | CyTOF+Bulk RNA-seq CITE-seq PBMCs | 36 (HK, 27 mild, 5 moderate, 4 severe) 40 (ATL) 24 influenza (ATL) | 45 HD (HK) 24 HD (ATL) | ↓ HLA-DR and expression of proinflammatory cytokines. Impaired response to stimulation with a bacterial or viral ligand cocktail | High |
| Kuri-Cervantes et al28 | Multiparametric flow cytometry | 35 (7 moderate, 28 severe), 7 recovered | 12 HD | ↓ HLA-DR expression in severe patients | High | |
| Lucas et al26 | Multiparametric flow cytometry | 113 (moderate 80, severe 33) | 108 HD | ↓ reduction of HLA-DR monocytes | Low | |
| Wen et al24 | Multiparametric flow cytometry | 10 recovered (5 early and 5 late) | 5 HD | ↑ CD14++ IL1β+ monocytes and IFN-activated monocytes | High | |
| Lee et al25 | ScRNA seq PBMCs | 8 COVID-19 (severe, mild, asymptomatic), 5 Influenza | 4 HD | The TNF/IL-1β-driven inflammatory response was dominant in COVID-19 across all types of cells among PBMCs | HIgh | |
| Silvin et al23 | Cy-TOF, single cell RNA seq | 13 COVID-19 (mild 5, severe 8) | 25 HD | ↑ CD14HighCD16High intermediate monocytes in patients with mild COVID-19 vs severe or HD | High | |
| Schult-Schrepping et al22 | Cy-TOF, single cell RNA seq, flow cytometry | 58 (40 COVID-19, 8 influenza) | 10 HD | ↑ inflammatory HLA-DRhiCD11chi CD14+ monocytes with an interferon-stimulated gene signature in mild forms ↑ HLA-DRhiCD11chi monocytes in severe forms ↓ expression of CD11c and HLA-DRA and HLA-DRB1 early and sustained ↑ CD226+ CD69+ monocytes Dysfunctional HLA-DRloCD163hi and HLA-DRloS100Ahi CD14+ in severe forms | High | |
| Dendritic cells | Arunachalam et al27 | Cy-TOF+Bulk RNA-seq CITE-seq PBMCs | 36 (HK, 27 mild, 5 moderate, 4 severe) 40 (ATL) 24 influenza (ATL) | 45 HD (HK) 24 HD (ATL) | ↓ pDCs pool reduced Impaired mTOR signalling and IFN-a production in response to the TLR stimuli and TNF response. | High |
| Zhou et al32 | Multiparametric flow cytometry Patients DC cultures | Acute COVID-19 (6 severe and 11 mild) Convalescent COVID-19 (2 severe and 22 mild) | HD | ↑ monocytic myeloid-derived suppressive cells in acute patients vs HD ↓ CD11c+ cDCs decreased in convalescent patients ↓ CD86 expression vs HD but not HLA-DR | High | |
| T cells | Weistemeier et al30 | Multiparametric flow cytometry PBMCs | 30 mild | 10 HD | ↓ CD4+ No difference in any of the subsets (naïve (N) (CD45RO- CCR7+ CD28+), central memory (CM) (CD45RO+ CCR7+ CD28+), transitional memory (TM) (CD45RO+ CCR7 CD28+), effector memory (EM) (CD45RO+ CCR7- CD28-), and terminally differentiated effector (E) (CD45RO- CCR7- CD28-) ↓ CD8+ (↓ naïve, ↑ effector, effector memory and transitional memory cells) ↑ cytotoxic molecules secretion granzyme A in effector, effector memory, and transitional memory cells and granzyme and perforin in effector memory, and transitional memory cells More multifunctional effector and effector memory T cells | High |
| Kuri-Cervantes et al28 | Multiparametric flow cytometry PBMCs | 35 (7 moderate, 28 severe), 7 recovered | 12 HD | =across all groups | High | |
| Lucas et al26 | Multiparametric flow cytometry PBMCs | 113 (moderate 80, severe 33) | 108 HD | ↓ CD4+ and CD8+ | Low | |
| Wang et al31 | CyTOF PBMCs | 12 (4 mild, 5 severe, 3 critical) | 12 HD | ↑ CD4+ CD8+ double-positive T cells ↑ naïve CD4+ T cells ↑ TGF-β+ CD28- naïve CD4+ T cells | Unclear | |
| Wen et al24 | Multiparametric flow cytometry | 10 recovered (5 early and 5 late) | 5 HD | ↓ CD8+ T cells ↓ effector memory CD8+ T cell ↑CD4+ T cells, the ratio of central memory CD4+ T cells was significantly higher ↓ naïve CD4+ T cells, Tregs and effector memory CD4+ (especially in the early recovery group) T cell expansion decreased in the early recovery group | High | |
| Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | ↓ CD4+ and CD8+ =TCR α/β– and γ/δ–positive T lymphocytes, across groups ↑ T central memory (CD45RA– CCR7+) cells =naïve (CD45RA+ CCR7+), T effector memory (CD45RA– CCR7–), T effector memory CD45RA+ (CD45RA+ CCR7–), and HLA-DR+ cells across groups ↓ naïve (CD45RA+ CCR7+) and T central memory (CD45RA–CCR7+) cells ↑ T effector memory (CD45RA+ CCR7–) and senescent (CD57+) CD8+ T cells =T effector memory (CD45RA– CCR7–) and HLA-DR+ CD8+ T cells across groups ↑ IL-2-producing CD4+ T cells and ↓ IL-2-producing CD8+ T lymphocytes and IFN-γ-producing CD4+ and CD8+ T cells ↓ IL-2+ IFN-γ+ TNF-α+ and IL-2+ IFN-γ+ TNF-α– CD8+ (polyfunctional) T cell | Unclear | |
| Odak et al34 | Multiparametric flow cytometry | 30 (15 severe) | None | ↑ CD4+ effector/effector memory (CD45RA− CD62L−), ↓ CD4+ terminally differentiated cells (CD45RA+ CD62 L−) ↑ CD8 naïve T cells ↓ CD8 effector/effector memory cells, CD8 central memory and CD8t effector memory ↑ naïve-like γδ (γδ naïve-l) cells ↓ in effector-like γδ (γδeff-l) | High | |
| Song et al33 | Multiparametric flow cytometry | 41 (29 mild, 12 severe) | None | ↑ activated CD38+ CD8+ T cells, HLA-DR+ CD8+ T cells and CD38+ HLA-DR+ CD8+ T cells =CD38+ CD4+ T cells and HLA-DR+ CD4+ T cells among groups | High | |
| Zhou et al32 | Multiparametric flow cytometry Patients DC cultures | Acute COVID-19 (6 severe and 11 mild) Convalescent COVID-19 (2 severe and 22 mild) | HD | ↑ PD-1 expression in CD4 T-cell central memory and effector memory CD4 T cells have ↓ polyfunctionality for releasing both IFN-γ and TNF-α in vitro in acute patients effector memory and CD45RA+ effector CD8 T cells ↓ polyfunctionality for releasing both IFN-γ and TNF-α effector memory and CD45RA+ effector CD8 T cells ↓ for granzyme B and perforin | High | |
| NK cells | Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | ↓ NK cells ↓ perforin and granzyme A | Unclear |
| Wen et al24 | Multiparametric flow cytometry | 10 recovered (5 early and 5 late) | 5 HD | ↓ NK cells | High | |
| B cells | Wen et al24 | Multiparametric flow cytometry | 10 recovered (5 early and 5 late) | 5 HD | Plasma cells ↓ naïve B cells | High |
| Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | = naive (IgD+ CD27–),memory-nonswitched (IgD+ CD27+), memory-switched (IgD– CD27+), and Blymphocytes and plasmablasts (CD27hiCD38hi)↓ transitional (IgMhiCD38hi) B lymphocytes | Unclear | |
| COVID-19 severe vs healthy donors | ||||||
| Monocytes | Lee et al25 | Single cell RNA seq PBMCs | 8 COVID-19 (severe, mild, asymptomatic), 5 influenza | 4 HD | ↑ classical monocytes ↓ DCs, non-classical monocytes, intermediate monocytes IFN-I-driven signatures in addition to TNF/IL-1β-driven inflammation | High |
| Silvin et al23 | Cy-TOF, single cell RNA seq | 13 COVID-19 (mild 5, severe 8) | 25 HD | ↓ non-classical CD14LowCD16High monocytes ↓ the expression of HLA-DR on classical monocytes | High | |
| T cells | Kuri-Cervantes et al28 | Multiparametric flow cytometry | 35 (7 moderate, 28 severe), 7 recovered | 12 HD | ↓ CD4+ and CD8+ ↓ CD8+ mucosal-associated invariant T cells (MAIT cells) ↓ innate lymphoid cells (ILCs) =in recovered and non-recovered populations | High |
| NK cells | Kuri-Cervantes et al28 | Multiparametric flow cytometry | 35 (7 moderate, 28 severe), 7 recovered | 12 HD | ↓ NK cells especially of both CD56brightCD16− and CD56dimCD16 populations in severe patients and ↓ circulating CD16+ NK cells | High |
| Odak et al34 | Multiparametric flow cytometry | 30 (15 severe) | None | ↓ NK, NKT, γδ- T cells | High | |
| B cells | Kuri-Cervantes et al28 | Multiparametric flow cytometry | 35 (7 moderate, 28 severe), 7 recovered | 12 HD | ↑ plasmablasts (p<0.0001) In the non-plasmablast B cell population: ↓ CD21+ CD27+ ↑ CD21− CD27− non-plasmablasts Profound oligoclonal expansion Same in both recovered and non-recovered patient populations | High |
| COVID-19 severe vs mild | ||||||
| T cells | Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | ↓ CD4+ without differences in subpopulation =CD8+ total populations but ↓ T effector memory (CD45RA–CCR7–) and ↑ T effector memory CD45RA+ CCR7) cells other subpopulations = =polyfunctional T cells | Unclear |
| Odak et al34 | Multiparametric flow cytometry | 30 (15 severe) | None | ↓ CD8+ ↓Treg ↓ effector/effector memory (CD45RA− CD62L−) | High | |
| Song et al33 | Multiparametric flow cytometry | 41 (29 mild, 12 severe) | None | ↓ CD4+ and CD8+ T cells ↑ PD-1+ CD8+ T cells in severe patients ↑ TIM-3+ CD8+ T cells and TIM-3+ CD4+ T cells ↑ PD-1 expression on CD38+ HLA-DR+ CD4+ T and CD38+ HLA-DR+ CD8+ T cells | Low | |
| NK cells | Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | ↓ NK cells ↓ granzyme A | Unclear |
| Odak et al34 | Multiparametric flow cytometry | 30 (15 severe) | None | ↓ NK, NKT, γδ- T cells | High | |
| COVID-19 severe vs mild to moderate | ||||||
| Dendritic cells | Lee et al25 | Single cell RNA seq PBMCs | 8 COVID-19 (severe, mild, asymptomatic), 5 influenza | 4 HD | ↓ DCs in the severe group | High |
| Kuri-Cervantes et al28 | Multiparametric flow cytometry | 35 (7 moderate, 28 severe), 7 recovered | 12 HD | ↓ conventional (CD11c+ CD123lo/−) and plasmacytoid (CD11c− CD123+) compared with moderate disease and HDs | High | |
| COVID-19 active vs recovered | ||||||
| T cells | Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | ↓ CD4+ without differences in subpopulation =CD8+ total populations but ↓ T effector memory (CD45RA–CCR7–) and ↑ T effector memory CD45RA+ CCR7) cells other subpop = =polyfunctional T cells | Unclear |
| Odak et al34 | Multiparametric flow cytometry | 30 (15 severe) | None | ↓ CD8+ ↓ Treg ↓ effector/effector memory (CD45RA− CD62L−) | High | |
| NK cells | Mazzoni et al29 | Multiparametric flow cytometry | 30 (13 severe) | None | ↓ NK cells ↓ granzyme A | Unclear |
| Odak et al34 | Multiparametric flow cytometry | 30 (15 severe) | None | ↓ NK, NKT, γδ T cells | High | |
| COVID-19 Convalescent severe vs convalescent mild | ||||||
| T cells | Zhang et al101 | Multiparametric flow cytometry | 5 severe and 4 mild | 12 HD | ↑ CD8+ effector memory (TEM) cells vs HD ↓ MAIT cells ↑ CD8+ T effector memory cells re-expressing CD45RA (named CD8+ terminal effector cells in severe disease) | High |
| Immunotypes associated with disease severity | ||||||
| Mathew et al35 | Multiparametric flow cytometry | 125 hospitalised, 36 recovered | 60 HD | Immunotype 1: Activated CD4 and CD8 T effector memory cells, ↓ circulating follicular helper cells, hyperactivated or exhausted CD8 T cells and plasmablasts Positively correlated with disease severity Immunotype 2: Not correlated with disease severity Immunotype 3: No activated T or B cells. Negatively correlated with disease severity. | ||
ATL, Atlanta; CITE-seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing; CyTOF, cytometry by time of flight; gMDSC, granulocytic myeloid derived suppressor cells; HD, healthy donor; HK, Hong-Kong; HLA-DR, Human Leucocyte Antigen – DR isotype; IFN, interferon; IL, interleukine; ITGAM, integrin alpha M; LDN, low density neutrophils; mTOR, mechanistic target of rapamycin; NK, natural killer; PBMCs, peripheral blood mononuclear cells; RNA, ribonucleic acid; RoB, risk of bias; TLR, Toll-like receptor; TNF, tumour necrosis factor.