Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

doi:10.1016/j.cell.2020.09.038

. 2020 Nov 12;183(4):996-1012.e19.

doi: 10.1016/j.cell.2020.09.038. Epub 2020 Sep 16.

Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

Carolyn Rydyznski Moderbacher¹, Sydney I Ramirez², Jennifer M Dan², Alba Grifoni¹, Kathryn M Hastie¹, Daniela Weiskopf¹, Simon Belanger¹, Robert K Abbott¹, Christina Kim¹, Jinyong Choi¹, Yu Kato¹, Eleanor G Crotty¹, Cheryl Kim³, Stephen A Rawlings⁴, Jose Mateus¹, Long Ping Victor Tse⁵, April Frazier¹, Ralph Baric⁶, Bjoern Peters¹, Jason Greenbaum¹, Erica Ollmann Saphire², Davey M Smith⁴, Alessandro Sette⁷, Shane Crotty⁸

Affiliations

¹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
² Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
³ Flow Cytometry Core Facility, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
⁴ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
⁵ Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁶ Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁷ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA. Electronic address: alex@lji.org.
⁸ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA. Electronic address: shane@lji.org.

PMID: 33010815
PMCID: PMC7494270
DOI: 10.1016/j.cell.2020.09.038

Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

Carolyn Rydyznski Moderbacher et al. Cell. 2020.

. 2020 Nov 12;183(4):996-1012.e19.

doi: 10.1016/j.cell.2020.09.038. Epub 2020 Sep 16.

Authors

Affiliations

¹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
² Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
³ Flow Cytometry Core Facility, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
⁴ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
⁵ Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁶ Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁷ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA. Electronic address: alex@lji.org.
⁸ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA. Electronic address: shane@lji.org.

PMID: 33010815
PMCID: PMC7494270
DOI: 10.1016/j.cell.2020.09.038

Abstract

Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4⁺ and CD8⁺ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4⁺ and CD8⁺ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4⁺ and CD8⁺ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4⁺ T cell, CD8⁺ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.

Keywords: CD4; CD8; CXCL10; IP-10; Spike; T cells; adaptive immunity; antibody; coronavirus; epitopes; neutralizing antibodies.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests A.S. is a consultant for Gritstone, Flow Pharma, and Avalia. S.C. is a consultant for Avalia.

Figures

**Figure 1**
SARS-CoV-2 Antibody Responses in COVID-19 Subjects (A–C) Plasma antibody titers to SARS-CoV-2 S RBD (A) IgG, (B) IgA, and (C) IgM, divided into unexposed n = 15, acute (Ac) n = 28, and convalescent (Co) n = 15. (D) SARS-CoV-2 RBD IgG correlates with RBD IgA. (E–G) Plasma ELISA titers to SARS-CoV-2 S (E) IgG, (F) IgA, and (G) IgM. (H) S IgG correlation with RBD IgG. (I–K) Plasma ELISA titers to SARS-CoV-2 Nucleocapsid (N) protein (I) IgG, (J) IgA, and (K) IgM. (L) N IgG correlation with S IgG. (M) Pseudovirus (PSV) neutralizing antibody titers in unexposed, acute, and convalescent COVID-19 samples. (N) PSV neutralizing antibody titers correlated with RBD IgG titers. (O and P) Both (O) RBD IgG and (P) PSV neutralizing Ab titers were detectable in most acute and all convalescent COVID-19 cases at all time points tested. The dotted line indicates LOD. Geometric mean titers with geometric SDs are indicated. Acute (Ac) = Red, Convalescent (Co) = black, Unexposed = gray. White = all COVID-19 (acute and convalescent). ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001, NS = not significant. See also Figure S1.

**Figure 2**
SARS-CoV-2-Specific CD4⁺ T Cell Responses (A) Representative flow cytometry gating of AIM⁺ (OX40⁺surfaceCD40L⁺) CD4⁺ T cells. (B) Percentage of background subtracted SARS-CoV-2-specific total CD4⁺ T cells quantified by AIM after stimulation with MP_R (Non-Spike), S (Spike), M (Membrane), or N (Nucleocapsid) peptide pools in unexposed (n = 15), acute COVID-19 (n = 30) and convalescent COVID-19 (n = 15). (C and D) Percentage of background subtracted combined MP_R, S, M, and N SARS-CoV-2-specific CD4⁺ T cells by AIM assay by (C) cohort and (D) by days PSO. Combined AIM responses were calculated as the sum of the CD4⁺ AIM response to background-subtracted individual peptide megapools. Statistics in (D) are reported for unexposed, convalescent, and acute samples. (E and F) ICS of SARS-CoV-2-specific CD4⁺ T cells quantified by co-expression of (E) CD40L⁺IFNγ⁺ or (F) CD40L⁺IL-2⁺ after stimulation with SARS-CoV-2 peptide pools in unexposed (n = 8), acute COVID-19 (n = 14) and convalescent COVID-19 samples (n = 11). (G and H) Cytokines IFNγ (G) and IL-2 (H) in the supernatants after stimulation with SARS-CoV-2 or CMV peptide pools in unexposed (n = 15), acute COVID-19 (n = 22), convalescent COVID-19 (n = 15), and CMV⁺ controls (n = 23). The black dotted line delineates background signal as determined by the unexposed controls. (I) Representative flow cytometry of SARS-CoV-2-specific (OX40⁺CD40L⁺) CD4⁺ T cells (blue dots) overlaid on total CD4⁺T cells (black dots). (J) Percentage of SARS-CoV-2-specific cT_FH cells in acute COVID-19 (n = 22) or convalescent COVID-19 (n = 15) samples that had a positive total CD4⁺ AIM response (> 0.04%) following stimulation with the SARS-CoV-2 S megapool (MP), or the total non-antigen-specific CXCR5⁺ CD4⁺ T cells in unexposed controls (n = 15, gray dots) (median displayed). (K) Representative fluorescence-activated cell sorting (FACS) plots of CXCR3 and CCR6 staining in total cT_FH (CXCR5⁺CD4⁺ cells) in unexposed donors or S-specific AIM⁺ (OX40⁺CD40L⁺) CD4⁺ T cells in acute and convalescent donors. (L and M) Frequency of (L) CXCR3 and/or CCR6 expressing S-specific AIM⁺ cells out of total CD4⁺ T cells in acute or convalescent samples or non-antigen-specific CXCR5⁺CD4⁺ cT_FH in unexposed samples (n = 15) and (M) CXCR5⁺ S-reactive AIM⁺ cells out of total CD4⁺ T cells in acute donors (n = 26 samples) or convalescent donors (n = 15 samples). Unless otherwise stated, the black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. Pink dots denote samples where two or more peptide pools were not run due to cell numbers. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001, NS = not significant. See also Figure S2, Table S4, and Table S5.

**Figure S2**
SARS-CoV-2-Specific CD4⁺ T Cell Responses, Related to Figure 2 (A) Gating strategy for identification of SARS-CoV-2-antigen-specific CD4⁺ T cells. (B) % of OX40⁺4-1BB⁺ CD4⁺ T cells specific for SARS-CoV-2 MP_R, S, M, N peptide megapools by AIM (C) Combined % Ox40⁺4-1-BB⁺ CD4⁺ T cells across all SARS-CoV-2 peptide megapools by AIM. The black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. Pink dots denote samples where two or more peptide pools were not run due to cell numbers. (D-F) Amount (pg/mL) of (D) IL-5 (E), IL-13 (F), and IL-17 in the AIM supernatants after stimulation with MP_R, S, M, N, and CMV peptide pools. The black dotted line delineates background signal as determined by the unexposed controls. Acute (Ac) = Red, Convalescent (Co) = black, Unexposed (Unexp) = gray. ^∗p < 0.05, ^∗∗p < 0.01, NS = not significant.

**Figure 3**
SARS-CoV-2-Specific CD8⁺ T Cell Responses (A) Sample flow cytometry gating of AIM (CD69⁺4-1BB⁺) CD8⁺ T cells. (B) Percentage of background subtracted SARS-CoV-2-specific total CD8⁺ T cells via AIM assay after stimulation with CD8_A/B, MP_R (Non-Spike), S (Spike), M (Membrane), N (Nucleocapsid) peptide pools in unexposed (n = 15), acute COVID-19 (n = 30) and convalescent COVID-19 (n = 15). (C and D) Percentage of background subtracted combined CD8-A/B, R, S, M, and N SARS-CoV-2-specific total CD4⁺ T cells by AIM assay (C) by cohort and (D) by days PSO. Combined AIM responses were calculated as the sum of the CD8⁺ AIM response to background-subtracted individual peptide megapools. Statistics in (D) are reported for unexposed, acute, and convalescent samples. (E) Quantitation of IFNγ in supernatants after stimulation with peptide pools unexposed (n = 15), acute COVID-19 (n = 21), and convalescent COVID-19 (n = 15). The black dotted line delineates background signal as determined by the unexposed controls. (F) Percentage of background subtracted SARS-CoV-2-specific total CD8⁺ T cells quantified by expression of IFNγ⁺ by ICS. (G) Representative flow cytometry gating of IFNγ⁺GzmB⁺ CD8⁺ T cells in acute and convalescent COVID-19 samples. (H) Percentage of IFNγ⁺ CD8⁺ T cells expressing granzyme B (GzmB), TNFα, or IL10 by ICS in unexposed (n = 8), acute COVID-19 (n = 14) and convalescent COVID-19 (n = 11). Unless otherwise stated, the black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. Pink dots denote samples where two or more peptide pools were not run due to cell numbers. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001, NS = not significant. See also Figure S3, Table S4, and Table S5.

**Figure S3**
SARS-CoV-2-Specific CD8+ T Cell Responses, Related to Figure 3 (A) Gating strategy for identification of SARS-CoV-2-antigen-specific CD8⁺ T cells. (B) Percentage of background subtracted SARS-CoV-2-specific total CD8⁺ T cells quantified by co-expression of IFNg and granzyme B (GzmB) by ICS in unexposed (n = 8), acute COVID-19 (n = 11) and convalescent COVID-19 (n = 11). The black dotted line indicates LOD. Acute (Ac) = Red, Convalescent (Co) = black, Unexposed (Unexp) = gray. ^∗p < 0.05, ^∗∗p < 0.01. NS = not significant.

**Figure 4**
Coordinated Adaptive Immune Responses to SARS-CoV-2 (A) Correlation of SARS-CoV-2-specific CD4⁺ T cells and RBD IgG. (B) Correlation of SARS-CoV-2-specific CD8⁺ T cells and RBD IgG. (C) Correlation of SARS-CoV-2-specific CD4⁺ and CD8⁺ T cells. (D) PSV neutralizing antibody titers over time for acute COVID-19 subjects with paired blood samples. Open circles denote other acute COVID-19 samples. Unexposed controls (n = 15), acute COVID-19 (n = 26), and convalescent COVID-19 (n = 15). The black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. Pink dots denote samples where two or more peptide pools were not run due to cell numbers. (E) Association between SARS-CoV-2 PSV-neutralizing antibodies and peak disease severity. (F and G) Association between (F) SARS-CoV-2-specific CD4⁺ T cells and (G) SARS-CoV-2-specific CD8⁺ T cells (“Low” < 0.1%, “High” > 0.1% combined AIM⁺) and COVID-19 peak disease severity. (H) Association between ADIM score and COVID-19 peak disease severity. Acute COVID-19 samples (n = 26) and convalescent COVID-19 samples (n = 26). Statistics for (A–C) are reported for unexposed, convalescent, and acute samples. ^∗p < 0.05, ^∗∗p < 0.01, NS = not significant. See also Figure S4 and Data S1.

**Figure S4**
Coordinated Adaptive Immune Responses, Related to Figure 4 (A-B) PSV neutralizing titer (A) and (B) percentage of SARS-CoV-2-specific T_FH cells in samples that had a positive total CD4⁺ AIM response (> 0.04%) following stimulation with the SARS-CoV-2 S MP, or the total CXCR5⁺ CD4⁺ T cells in unexposed controls in additional unexposed donors (n = 12) and convalescent COVID-19 donors (n = 11). (C-D) Flow cytometry of AIM⁺ CD4⁺ T cell response (C) and AIM+ CD8⁺ T cells response (D) in donor C4844. (E) Frequency of ADIM observed in the cohort. (F) Correlation of SARS-CoV-2-specific total CD4⁺ T cells by OX40⁺CD40L⁺ AIM assay and days PSO, stratified into Immunotypes. Statistics are reported for unexposed, convalescent and acute samples. (G) Frequency of ADIM by gender. (H-I) Combined CD4⁺ AIM data based on day PSO from Fig. 2D and 3D with responses labeled for specific donors of interest. Statistics in (H-I) are reported for unexposed, convalescent and acute samples. The black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. Pink dots denote samples where two or more peptide pools were not run due to cell numbers. NS = not significant, ^∗∗∗p < 0.001, geometric mean with geometric SD displayed in S4A, median displayed in S4B.

**Figure S5**
Plasma Cytokines and Immunophenotyping, Related to Figure 5 (A-M) Quantitation of plasma cytokine levels from acute (n = 24) and unexposed (n = 15) donors: (A) CXCL10, (B) IL-8, and (C) IL-6. (D) IL-1b, (E) TNFa, (F) IFNl1, (G) IL12p70, (H) IFNa2, (I) IFNl2, (J) GM-CSF, (K) IFNb, (L) IL-10, (M) IFNg. (N) Correlation of CD3^-CD19^- PBMCs and peak disease severity. Statistics are reported for convalescent and acute samples. (O-P) Correlation of (O) activated CD4 T cells with combined AIM+ CD4 T cells and (P) activated CD8 T cells with combined AIM+ CD8 T cells across all donors. Statistics are reported for unexposed, convalescent and acute samples. (Q) Correlation of (CD38^hiCD20^-CD19⁺) plasmablasts with RBD IgG titers. Statistics are reported for unexposed and acute samples. (R) Gating strategies for plasmablasts and T cell subtypes. The black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. Pink dots denote samples where two or more peptide pools were not run due to cell numbers. Acute (Ac) = Red, Convalescent = black, Unexposed (Unexp) = gray. ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001, NS = not significant.

**Figure S6**
Correlations of the Immune Response with Disease Severity in COVID-19 Donors, Related to Figure 6 Correlogram of all COVID-19 cases. Spearman R values are shown from red (−1.0) to blue (1.0); r values are indicated by color and square size. Peak COVID-19 disease severity (“Peak disease”) is the bottom row. Additional information on feature names are described in the STAR Methods. Blank fields with dots indicate lack of signal. p values are indicated by white asterisks. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001.

**Figure 5**
Associations of Adaptive Immune Response Features with COVID-19 Severity (A) Correlogram of acute COVID-19 donors. Spearman rank order correlation values (r) are shown from red (−1.0) to blue (1.0); r values are indicated by color and square size. Blank fields with black dots indicate lack of signal. p values are indicated by white asterisks. The teal triangle denotes SARS-CoV-2 antibody features, magenta triangle denotes SARS-CoV-2-specific CD4⁺ T cells features, and orange triangle denotes SARS-CoV-2-specific CD8⁺ T cell features. Purple rectangles denote coordinated adaptive immune response features. The dark green line denotes select inflammatory cytokines. Peak COVID-19 disease severity (“Peak disease”) is the bottom row. Additional information on feature names are described in the STAR Methods. (B) Correlation of Ki67⁺CD38⁺HLA-DR⁺ CD4⁺ T cells (as percentage of total CD4⁺ T cells) with SARS-CoV-2-specific (combined AIM⁺) CD4⁺ T cells. (C) Correlation of Ki67⁺CD38⁺HLA-DR⁺ CD8⁺ T cells (as percentage of total CD8⁺ T cells) with SARS-CoV-2-specific (combined AIM⁺) CD8⁺ T cells. (D) Correlation of activated (ICOS⁺PD-1^hi) T_FH cells (as percentage of total CD4⁺ T cells) with SARS-CoV-2-specific (combined AIM⁺) T_FH (CXCR5⁺CD4⁺) cells. (E) Correlation of SARS-CoV-2 PSV-neutralizing antibody titer and percentage plasmablasts (CD38^hiCD20^- of CD19⁺ B cells). Unexposed controls (n = 15), acute COVID-19 (n = 26) displayed. Statistics reported for (B–E) are reported for unexposed and acute donors. The black dotted line indicates LOD; the green dotted line demarcates marginal responses as determined by unexposed donor responses. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001. See also Figure S5, Table S3, and Data S1.

**Figure 6**
Association of Age and Naive T Cells with COVID-19 Severity (A and B) Correlograms of acute donors < 65 years (A) and ≥ 65 years (B). As in Figure 5, Spearman r correlation values are shown from red (−1.0) to blue (1.0); r values are indicated by color and square size. Blank fields with dots indicate lack of signal. p values are indicated by white asterisks. Also, as in Figure 5, the teal triangle denotes SARS-CoV-2 antibody features, magenta triangle denotes SARS-CoV-2-specific CD4⁺ T cells features, and orange triangle denotes SARS-CoV-2-specific CD8⁺ T cell features. Purple rectangles denote coordinated adaptive immune response features. Peak COVID-19 disease severity (“Peak disease”) is the bottom row. Select inflammatory cytokines are labeled with a dark green line. (C) Correlation of age and peak disease severity. Statistics for full dataset shown are in black; statistics for acute COVID-19 cases are in red. (D) Correlation of naive CD4⁺ T cells (as percentage of total CD4⁺ T cells) with age. Statistics for full dataset are shown in black; statistics for all COVID-19 cases (convalescent and acute) are in blue; statistics for acute COVID-19 cases are in red. (E) Correlation of naive CD4⁺ T cells (as percentage of total CD4⁺ T cells) and peak disease severity. Statistics for all COVID-19 cases (convalescent and acute) are in blue; statistics for acute COVID-19 cases are in red. (F) Correlation of naive CD8⁺ T cells (as percentage of total CD8⁺ T cells) with age. Statistics for full dataset are shown in black; statistics for all COVID-19 cases (convalescent and acute) are in blue; statistics for acute COVID-19 cases are in red. (G) Correlation of naive CD8⁺ T cells (as percentage of total CD8⁺ T cells) and peak disease severity. Statistics for all COVID-19 cases (convalescent and acute) are in blue; statistics for acute COVID-19 cases are in red. Unexposed controls in gray (n = 67), convalescent COVID-19 in black (n = 15), acute COVID-19 in red (n = 26) displayed. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001. See also Figures S6 and S7, Table S3, and Data S1.

**Figure S7**
Uncoordinated Adaptive Immunity in the Elderly, Related to Figures 6 and 7 (A-B) Correlograms of all acute COVID-19 cases age < 75 (A) and $\geq$ 75 (B). Spearman R values are shown from red (−1.0) to blue (1.0). Blank fields with dots indicate lack of signal. (C) Correlogram of curated markers of adaptive immune responses in acute COVID-19 subjects (top) and all COVID-19 subjects (bottom). Spearman r correlation values are shown from red (−1.0) to blue (1.0). ^∗p < 0.05, ^∗∗p < 0.001, ^∗∗∗p < 0.0001. Thick black squares outlining a field indicate adjusted FDR < 0.05. (D-E) Gating strategies for (D) naive CD8⁺ and (E) CD4⁺ T cells for acute and donors < 75 years old and $\geq$ 75 years old, and convalescent donors. (F) Secreted IFNg (pg/mL) after SARS-CoV-2 CD8A/B MP stimulation, versus peak COVID-19 disease severity, acute samples (n = 21). Statistics in (F) are reported for acute samples (shown in red). ^∗p < 0.05, ^∗∗p < 0.001, ^∗∗∗p < 0.0001.

**Figure 7**
Associations of COVID-19-Specific CD4 and CD8 T Cell Responses and Disease Severity (A) Frequency of IFNγ⁺ CD8⁺ T cells in response to CD8A/B MP ICS, versus peak COVID-19 disease severity, acute donors (n = 11 samples). Dotted line indicates LOD. (B–D) Associations between peak COVID-19 disease severity and number per million PBMC of (B) AIM⁺ CD8⁺ T cells (CD69⁺4-1BB⁺CD8⁺), (C) AIM⁺ CD4⁺ T cells (OX40⁺surfaceCD40L⁺), or (D) AIM⁺ cT_FH cells (OX40⁺CD40L⁺CXCR5⁺CD4⁺) across all SARS-CoV-2 peptide-specific MPs, acute samples (n = 26), and convalescent samples (n = 15). (E and F) Frequency of (E) CXCR3^-CCR6⁺ S-specific (AIM⁺) CD4⁺ T cells and (F) CXCR5⁺CXCR3^-CCR6⁺ S-specific (AIM⁺) cT_FH CD4⁺ T cells versus peak disease severity, acute samples (n = 26), and convalescent samples (n = 15). Dotted line denotes LOD. Statistics for acute COVID-19 cases are in red; statistics for all COVID-19 cases (convalescent and acute) are in black. See also Figure S7 and Data S1.

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[1] Amanat F., Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020;52:583–589. - PMC - PubMed

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Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

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Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

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