TNF-α+ CD4+ T cells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies

Kattria van der Ploeg, Adam S Kirosingh, Diego A M Mori, Saborni Chakraborty, Zicheng Hu, Benjamin L Sievers, Karen B Jacobson, Hector Bonilla, Julie Parsonnet, Jason R Andrews, Kathleen D Press, Maureen C Ty, Daniel R Ruiz-Betancourt, Lauren de la Parte, Gene S Tan, Catherine A Blish, Saki Takahashi, Isabel Rodriguez-Barraquer, Bryan Greenhouse, Upinder Singh, Taia T Wang, Prasanna Jagannathan, Kattria van der Ploeg, Adam S Kirosingh, Diego A M Mori, Saborni Chakraborty, Zicheng Hu, Benjamin L Sievers, Karen B Jacobson, Hector Bonilla, Julie Parsonnet, Jason R Andrews, Kathleen D Press, Maureen C Ty, Daniel R Ruiz-Betancourt, Lauren de la Parte, Gene S Tan, Catherine A Blish, Saki Takahashi, Isabel Rodriguez-Barraquer, Bryan Greenhouse, Upinder Singh, Taia T Wang, Prasanna Jagannathan

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4+ T cells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4+ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4+ T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing interferon gamma (IFNγ) to tumor necrosis factor alpha (TNF-α) from 5 days to 4 months post-enrollment, with IFNγ-IL-21-TNF-α+ CD4+ T cells the predominant population detected at later time points. Greater percentages of IFNγ-IL-21-TNF-α+ CD4+ T cells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7 months post-infection (⍴ = 0.4, p = 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ- and TNF-α-producing, spike-protein-specific CD4+ T cells. These data suggest that SARS-CoV-2-specific, TNF-α-producing CD4+ T cells may play an important role in antibody maintenance following COVID-19.

Trial registration: ClinicalTrials.gov NCT04331899.

Keywords: CD4; COVID-19; SARS-CoV-2; T cells; TNF-α; Tfh; antibodies; cytokines; longitudinal; neutralizing antibodies.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Identification of four distinct SARS-CoV-2-specific CD4+ T cell subsets that differ between S- and MN-protein stimulation PBMCs of COVID-19 outpatients on day 28 post-enrollment were stimulated with spike (S) or a combination of membrane (M) and nucleocapsid (N) proteins in vitro and were stained and analyzed by flow cytometry. (A and C) Representative flow plots of (A) cytokine-producing (TNF-ɑ, IFNγ, and IL-21) or (C) AIM-expressing (CD137+OX40+) CD45RA- CD4+ T cells that are stimulated with “media only” or MN or S proteins. (B) The absolute percentage (scatterplot; black line, median) of each individual combination of TNF-ɑ-, IFNγ-, and IL-21-producing non-naïve CD4+ T cells stratified by antigenic stimuli (red: MN, blue: S; n = 99). The pie charts show the relative proportion (mean) of each individual combination of cytokine-producing non-naïve CD4+ T cells (e.g., pie slice 4 represents TNF-ɑ+IFNγ-−IL-21−-) among the total population of antigen-specific cells, stratified by antigenic stimuli (MN: n = 102, S: n = 100). The p value shown under the pie charts is calculated using a partial permutation test. (D) Shown are absolute percentages of OX40+CD137+ CD45RA- CD4+ T cells stratified by antigenic stimuli with the black line indicating the median (n = 104). (B and D) p values shown above the scatterplots are calculated using Wilcoxon matched-pairs signed rank test. Values shown are background (media-only condition) subtracted. See also Figures S1–S3 and S5.
Figure 2
Figure 2
Kinetics of four distinct cytokine-producing SARS-CoV-2-specific CD4+ T cell populations over time and the density of CCR7 receptor expression on these populations (A and B) PBMCs from 24 COVID-19 outpatients sampled at days 5, 14, and 28 and month 4 (day 120) (n = 10 also sampled on day of enrollment [day 0]) were stimulated with MN (left) or S (right) proteins in vitro and were stained and analyzed by flow cytometry. (A) The mean and SEM of the absolute percentage of background-subtracted IFNγ-IL-21-TNF-ɑ+- (blue), IFNγ+IL-21-TNF-ɑ-- (yellow), IFNγ-IL-21+TNF-ɑ-- (red), or IFNγ+IL-21-TNF-ɑ+-producing non-naïve CD4+ T cells (green) of sequential timepoints post-enrollment are shown. These four populations were the dominant populations identified in Figure 1. (B) The relative proportion of each individual combination of background-subtracted, TNF-ɑ-, IFN-γ, and IL-21-producing non-naïve CD4+ T cells stratified by sequential days are depicted in the pie charts (mean). The p values indicated on top of the pie charts are calculated using the partial permutation test, which tests the association between MN- and S-protein stimulation of each indicated day post-enrollment. The p values in the tables indicate the significance of the associations between the different days post-enrollment calculated using the partial permutation test (left: MN-protein-stimulated T cells; right: S-protein-stimulated T cells). (C) Representative flow cytometry plots of CCR7- and CD45RA-expressing CD4+ T cells (left) with an overlay of MN-protein-specific IFNγ-IL-21-TNF-ɑ+- (blue), IFNγ+IL-21-TNF-ɑ-- (yellow), IFNγ-IL-21+TNF-ɑ--(red), or IFNγ+IL-21-TNF-ɑ+-producing non-naïve CD4+ T cells (green, right). (D) Mean fluorescence intensity (MFI) of CCR7 on MN- (left, n = 72) or S-protein-specific (right, n = 74) single positive TNF-ɑ- (blue), IFNγ- (yellow), IL-21- (red), or TNF-ɑ- and IFNγ-producing non-naïve CD4+ T cells (green) from day 28 post-enrollment. The p values were calculated using the Friedman test with Dunn’s multiple comparisons test (black line, median). See also Figures S1, S2, and S4–S6.
Figure 3
Figure 3
The kinetics of SARS-CoV-2-specific AIM+ CD4+, activated cTfh, and SARS-CoV-2-specific cTfh cell percentages and their correlation with cytokine-producing CD4+ T cells PBMCs of COVID-19 outpatients on days 5, 14, 28, and 120 post-enrollment were stimulated with MN or S proteins in vitro and were stained and analyzed by flow cytometry. (A) The kinetics of the absolute percentage of paired MN- (left, n = 22) or S- (right, n = 19) protein-stimulated AIM+ CD45RA- CD4+ T cells over time. (B) The gating strategy of PD-1+CXCR5+CD4+ (cTfh), PD-1+CXCR5+ICOS+CD4+ (ICOS+ cTfh), and PD-1+CXCR5+OX40+CD137+CD4+ (AIM+ cTfh) cells. (C and D) The kinetics of the absolute percentage of paired (C) cTfh (n = 21) and (D) ICOS+ cTfh (n = 21) cells of unstimulated cells (media only) are depicted. (E) The kinetics of the absolute percentage paired AIM+ cTfh cells stimulated with MN (left, n = 22) or S (right, n = 19) protein over time are shown. (A and C–E) The p values were calculated using the Friedman test with Dunn’s multiple comparisons test. (F) The heatmap shown depicts Spearman’s correlations (Benjamini-Hochberg corrected) between the percentages of MN- (left, n = 101) or S-protein-stimulated (right, n = 100) cTfh cell populations (cTfh, ICOS+ cTfh, and AIM+ cTfh) or AIM+ CD45RA- CD4+ T cells measured in AIM experiments and cytokine-producing non-naïve CD4+ T cells measured in ICS experiments. The measurements that are significantly associated are indicated by asterisks (∗p < 0.05, ∗∗∗p < 0.001). The scale bar indicates the Spearman's correlation rho (ρ). (G) Scatterplots comparing antigen-stimulated (MN: left/red, n = 101; S: right/blue, n = 100) IFNγ-IL-21-TNF-ɑ+-producing T cells with ICOS+ cTfh (top), AIM+ cTfh (middle), or AIM+ CD45RA- CD4+ T (bottom) cells are shown (n = 101). The rho (ρ) and p values were calculated using Spearman’s correlation (Benjamini-Hochberg corrected). The lines represent the fitted linear relationship between the indicated cell populations. See also Figure S1.
Figure 4
Figure 4
Late T cell responses are positively correlated with durability of antibody titers, while early T cell responses are not associated with the peak magnitude of antibody titers (A and C) In the heatmaps, Spearman’s correlations (Benjamini-Hochberg corrected) between indicated cTfh cell populations, AIM+ CD45RA- CD4+, and cytokine+ non-naïve CD4+ T cell data and antibody titers (S protein IgG binding [area under the curve (AUC) IgG] or neutralizing antibody (Neut) are shown. The measurements that are significantly associated are indicated by asterisks (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001). The scale bar indicates the Spearman's correlation rho (ρ). (A) Correlations are performed between indicated T cell data collected at day 5 post-enrollment and indicated antibody titers at day 28 post-enrollment. (B) Scatterplots comparing MN- (left/red) and S-protein-stimulated (right/blue) IFNγ-IL-21-TNF-ɑ+-producing non-naïve CD4+ T cells collected on day 5 (MN: n = 55; S: n = 51) post-enrollment with neutralizing antibody titers collected on day 28 post-enrollment are depicted. (C) Correlations are performed between indicated T cell data collected on day 28 post-enrollment and indicated antibody titers at day 28 or 210 post-enrollment. (D) Scatterplots comparing antigen-stimulated IFNγ-IL-21-TNF-ɑ+-producing non-naïve CD4+ T cells collected on day 28 (MN: n = 81; S: n = 78) post-enrollment with neutralizing antibody titers collected on day 28 post-enrollment are shown. (E) Scatterplots comparing antigen-stimulated IFNγ-IL-21-TNF-ɑ+-producing non-naïve CD4+ T cells (left, MN: n = 48, S: n = 47) or ICOS+ cTfh cells (right, MN: n = 52, S: n = 50) collected on day 28 with neutralizing antibody titers collected on day 210 post-enrollment are shown. (B, D, and E) The neutralizing antibody titers are presented in natural logarithm, and we added +1 to allow for inclusion of participants with no neutralizing activity. The rho (ρ) and p values were calculated using Spearman’s correlation (Benjamini-Hochberg corrected). The lines represent the fitted linear relationship between the indicated data. See also Figures S5 and S7.
Figure 5
Figure 5
Associations between early immune response and T cell responses on day 28 post-enrollment (A) Gene-Ontology-based immune pathways (left) and plasma proteins (right) associated with the absolute percentage of SARS-CoV-2-specific IFNγ-IL-21-TNF-ɑ+ non-naïve CD4+ T cells on day 28. (B) Scatterplots showing associations between the MCP-3 on day 0 or 5 and the percentage of SARS-CoV-2-specific IFNγ-IL-21-TNF-ɑ+ non-naïve CD4+ T cells on day 28. (C) Gene-Ontology-based immune pathways (left) and plasma proteins (right) associated with the absolute percentage of ICOS+ cTfh cells on day 28. (D) Scatterplots showing associations between the MCP-3 on day 0 or 5 and ICOS+ cTfh cells on day 28. (A and C) We used regression models to test the association while controlling for the sampling time of immune pathways or proteins (day 0 or 5) and the stimulation type (MN or S) of the T cell response. (B and D) The color of the points represents the stimulating antigens. The spearman correlations (rho [ρ]) between MCP-3 and the T cell percentages and the corresponding p values are reported. See also Tables S2 and S3.
Figure 6
Figure 6
mRNA vaccination boosts IFNγ+IL-21-TNF-ɑ-- and IFNγ+IL-21-TNF-ɑ+-producing CD4+ T cells and AIM+ cTfh cells PBMCs of COVID-19 outpatients on month 10 post-enrollment were stimulated with S or MN proteins in vitro and were stained and analyzed by flow cytometry. (A) The absolute percentage (scatterplot; black line, median) of each individual combination of TNF-ɑ-, IFNγ-, and IL-21-producing non-naïve CD4+ T cells stratified by vaccination status (closed triangle: unvaccinated, n = 20; open triangle: vaccinated, n = 20). Top panel depicts MN-protein-stimulated CD4+ T cells (red), and bottom panel depicts S-protein-stimulated CD4+ T cells (blue). p values shown above the scatterplots are calculated using the Mann Whitney test. The pie charts show the relative proportion (mean) of each individual combination of cytokine-producing non-naïve CD4+ T cells (e.g., pie slice 4 represents TNFa+IFNγ−IL-21−) among the total populaton of antigen-specifc cells, stratified by antigenic stimuli. The p value shown under the pie charts is calculated using a partial permutation test. (B) The ratio between month 10 and day 20 of the absolute percentage of IFNγ+IL-21-TNF-ɑ+- (IFN + TNF, left), IFNγ+IL-21-TNF-ɑ-- (IFNsp, middle), or IFNγ-IL-21-TNF-ɑ+-producing (TNFsp, right) non-naïve CD4+ T cells stimulated with the S protein is depicted (scatterplot; black line, median). (C) The absolute percentage (left) and the ratio between month 10 and day 28 of AIM+ (CD137+/OX40+) cTfh cells (right) stimulated with the MN (red) or S (blue) proteins and stratified by vaccination status are shown. (B and C) The p values shown are calculated using the Mann Whitney test. See also Figure S8.

References

    1. Chen Z., John Wherry E. T cell responses in patients with COVID-19. Nat. Rev. Immunol. 2020;20:529–536. doi: 10.1038/s41577-020-0402-6.
    1. Grifoni A., Weiskopf D., Ramirez S.I., Mateus J., Dan J.M., Moderbacher C.R., Rawlings S.A., Sutherland A., Premkumar L., Jadi R.S., et al. Targets of T Cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020;181:1489–1501. doi: 10.1016/j.cell.2020.05.015.
    1. Sette A., Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 2021;184:861–880. doi: 10.1016/j.cell.2021.01.007.
    1. Anand S., Montez-Rath M.E., Han J., Garcia P., Cadden L., Hunsader P., Kerschmann R., Beyer P., Boyd S.D., Chertow G.M., Parsonnet J. Serial SARS-CoV-2 receptor-binding domain antibody responses in patients receiving dialysis. Ann. Intern. Med. 2021;174:1073–1080. doi: 10.7326/m21-0256.
    1. Cromer D., Juno J.A., Khoury D., Reynaldi A., Wheatley A.K., Kent S.J., Davenport M.P. Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection. Nat. Rev. Immunol. 2021;21:395–404. doi: 10.1038/s41577-021-00550-x.
    1. Breton G., Mendoza P., Hägglöf T., Oliveira T.Y., Schaefer-Babajew D., Gaebler C., Turroja M., Hurley A., Caskey M., Nussenzweig M.C. Persistent cellular immunity to SARS-CoV-2 infection. J. Exp. Med. 2021;218:e20202515. doi: 10.1084/jem.20202515.
    1. Dan J.M., Mateus J., Kato Y., Hastie K.M., Yu E.D., Faliti C.E., Grifoni A., Ramirez S.I., Haupt S., Frazier A., et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021;371:eabf4063. doi: 10.1126/science.abf4063.
    1. Goel R.R., Painter M.M., Apostolidis S.A., Mathew D., Meng W., Rosenfeld A.M., Lundgreen K.A., Reynaldi A., Khoury D.S., Pattekar A., et al. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science. 2021;374:abm0829. doi: 10.1126/science.abm0829.
    1. Painter M.M., Mathew D., Goel R.R., Apostolidis S.A., Pattekar A., Kuthuru O., Baxter A.E., Herati R.S., Oldridge D.A., Gouma S., et al. Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination. Immunity. 2021;54:2133–2142.e3. doi: 10.1016/j.immuni.2021.08.001.
    1. Rodda L.B., Netland J., Shehata L., Pruner K.B., Morawski P.A., Thouvenel C.D., Takehara K.K., Eggenberger J., Hemann E.A., Waterman H.R., et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell. 2021;184:169–183.e17. doi: 10.1016/j.cell.2020.11.029.
    1. Tan A.T., Linster M., Tan C.W., Le Bert N., Chia W.N., Kunasegaran K., Zhuang Y., Tham C.Y.L., Chia A., Smith G.J.D., et al. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 2021;34:108728. doi: 10.1016/j.celrep.2021.108728.
    1. Wheatley A.K., Juno J.A., Wang J.J., Selva K.J., Reynaldi A., Tan H.-X., Lee W.S., Wragg K.M., Kelly H.G., Esterbauer R., et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 2021;12:1162. doi: 10.1038/s41467-021-21444-5.
    1. Zuo J., Dowell A.C., Pearce H., Verma K., Long H.M., Begum J., Aiano F., Amin-Chowdhury Z., Hoschler K., Brooks T., et al. Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection. Nat. Immunol. 2021;22:620–626. doi: 10.1038/s41590-021-00902-8.
    1. Cohen K.W., Linderman S.L., Moodie Z., Czartoski J., Lai L., Mantus G., Norwood C., Nyhoff L.E., Edara V.V., Floyd K., et al. Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells. Cell Rep. Med. 2021;2:100354. doi: 10.1016/j.xcrm.2021.100354.
    1. Jung J.H., Rha M.-S., Sa M., Choi H.K., Jeon J.H., Seok H., Park D.W., Park S.-H., Jeong H.W., Choi W.S., Shin E.C. SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells. Nat. Commun. 2021;12:4043. doi: 10.1038/s41467-021-24377-1.
    1. Peluso M.J., Deitchman A.N., Torres L., Iyer N.S., Munter S.E., Nixon C.C., Donatelli J., Thanh C., Takahashi S., Hakim J., et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms. Cell Rep. 2021;36:109518. doi: 10.1016/j.celrep.2021.109518.
    1. Corey L., Mascola J.R., Fauci A.S., Collins F.S. A strategic approach to COVID-19 vaccine R&D. Science. 2020;368:948–950. doi: 10.1126/science.abc5312.
    1. Thanh Le T., Andreadakis Z., Kumar A., Gómez Román R., Tollefsen S., Saville M., Mayhew S. The COVID-19 vaccine development landscape. Nat. Rev. Drug Discov. 2020;19:305–306. doi: 10.1038/d41573-020-00073-5.
    1. Weinreich D.M., Sivapalasingam S., Norton T., Ali S., Gao H., Bhore R., Musser B.J., Soo Y., Rofail D., Im J., et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with covid-19. N. Engl. J. Med. 2021;384:238–251. doi: 10.1056/nejmoa2035002.
    1. Addetia A., Crawford K.H.D., Dingens A., Zhu H., Roychoudhury P., Huang M.-L., Jerome K.R., Bloom J.D., Greninger A.L. Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with a high attack rate. J. Clin. Microbiol. 2020;58:e02107-20. doi: 10.1128/jcm.02107-20.
    1. Huang A.T., Garcia-Carreras B., Hitchings M.D.T., Yang B., Katzelnick L.C., Rattigan S.M., Borgert B.A., Moreno C.A., Solomon B.D., Trimmer-Smith L., et al. A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity. Nat. Commun. 2020;11:4704. doi: 10.1038/s41467-020-18450-4.
    1. Khoury D.S., Cromer D., Reynaldi A., Schlub T.E., Wheatley A.K., Juno J.A., Subbarao K., Kent S.J., Triccas J.A., Davenport M.P. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 2021;27:1205–1211. doi: 10.1038/s41591-021-01377-8.
    1. Crotty S. T follicular helper cell Biology: a decade of discovery and diseases. Immunity. 2019;50:1132–1148. doi: 10.1016/j.immuni.2019.04.011.
    1. Hale J.S., Ahmed R. Memory T follicular helper CD4 T cells. Front. Immunol. 2015;6:16. doi: 10.3389/fimmu.2015.00016.
    1. Sekine T., Perez-Potti A., Rivera-Ballesteros O., Strålin K., Gorin J.-B., Olsson A., Llewellyn-Lacey S., Kamal H., Bogdanovic G., Muschiol S., et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell. 2020;183:158–168. doi: 10.1016/j.cell.2020.08.017.
    1. Liao M., Liu Y., Yuan J., Wen Y., Xu G., Zhao J., Cheng L., Li J., Wang X., Wang F., et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 2020;26:842–844. doi: 10.1038/s41591-020-0901-9.
    1. Rydyznski Moderbacher C., Ramirez S.I., Dan J.M., Grifoni A., Hastie K.M., Weiskopf D., Belanger S., Abbott R.K., Kim C., Choi J., et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell. 2020;183:996–1012.e19. doi: 10.1016/j.cell.2020.09.038.
    1. Zhou R., To K.K.-W., Wong Y.-C., Liu L., Zhou B., Li X., Huang H., Mo Y., Luk T.-Y., Lau T.T.-K., et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity. 2020;53:864–877.e5. doi: 10.1016/j.immuni.2020.07.026.
    1. Braun J., Loyal L., Frentsch M., Wendisch D., Georg P., Kurth F., Hippenstiel S., Dingeldey M., Kruse B., Fauchere F., et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020;587:270–274. doi: 10.1038/s41586-020-2598-9.
    1. Peng Y., Mentzer A.J., Liu G., Yao X., Yin Z., Dong D., Dejnirattisai W., Rostron T., Supasa P., Liu C., et al. Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat. Immunol. 2020;21:1336–1345. doi: 10.1038/s41590-020-0782-6.
    1. Weiskopf D., Schmitz K.S., Raadsen M.P., Grifoni A., Okba N.M.A., Endeman H., van den Akker J.P.C., Molenkamp R., Koopmans M.P.G., van Gorp E.C.M., et al. Phenotype and kinetics of SARS-CoV-2–specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci. Immunol. 2020;5:eabd2071. doi: 10.1126/sciimmunol.abd2071.
    1. Seder R.A., Darrah P.A., Roederer M. T-cell quality in memory and protection: implications for vaccine design. Nat. Rev. Immunol. 2008;8:247–258. doi: 10.1038/nri2274.
    1. Eto D., Lao C., DiToro D., Barnett B., Escobar T.C., Kageyama R., Yusuf I., Crotty S. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One. 2011;6:e17739. doi: 10.1371/journal.pone.0017739.
    1. Rasheed M.A.U., Latner D.R., Aubert R.D., Gourley T., Spolski R., Davis C.W., Langley W.A., Ha S.-J., Ye L., Sarkar S., et al. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J. Virol. 2013;87:7737–7746. doi: 10.1128/jvi.00063-13.
    1. Boppana S., Qin K., Files J.K., Russell R.M., Stoltz R., Bibollet-Ruche F., Bansal A., Erdmann N., Hahn B.H., Goepfert P.A. SARS-CoV-2-specific circulating T follicular helper cells correlate with neutralizing antibodies and increase during early convalescence. PLoS Pathog. 2021;17:e1009761. doi: 10.1371/journal.ppat.1009761.
    1. Gong F., Dai Y., Zheng T., Cheng L., Zhao D., Wang H., Liu M., Pei H., Jin T., Yu D., Zhou P. Peripheral CD4+ T cell subsets and antibody response in COVID-19 convalescent individuals. J. Clin. Invest. 2020;130:6588–6599. doi: 10.1172/jci141054.
    1. Juno J.A., Tan H.-X., Lee W.S., Reynaldi A., Kelly H.G., Wragg K., Esterbauer R., Kent H.E., Batten C.J., Mordant F.L., et al. Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19. Nat. Med. 2020;26:1428–1434. doi: 10.1038/s41591-020-0995-0.
    1. Meckiff B.J., Ramírez-Suástegui C., Fajardo V., Chee S.J., Kusnadi A., Simon H., Eschweiler S., Grifoni A., Pelosi E., Weiskopf D., et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell. 2020;183:1340–1353.e16. doi: 10.1016/j.cell.2020.10.001.
    1. Neidleman J., Luo X., Frouard J., Xie G., Gill G., Stein E.S., McGregor M., Ma T., George A.F., Kosters A., et al. SARS-CoV-2-Specific T cells exhibit phenotypic features of helper function, lack of terminal differentiation, and high proliferation potential. Cell Rep. Med. 2020;1:100081. doi: 10.1016/j.xcrm.2020.100081.
    1. Jagannathan P., Andrews J.R., Bonilla H., Hedlin H., Jacobson K.B., Balasubramanian V., Purington N., Kamble S., de Vries C.R., Quintero O., et al. Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nat. Commun. 2021;12:1967. doi: 10.1038/s41467-021-22177-1.
    1. Jacobson K.B., Purington N., Parsonnet J., Andrews J., Balasubramanian V., Bonilla H., Edwards K., Desai M., Singh U., Hedlin H., Jagannathan P. Inflammatory but not respiratory symptoms are associated with ongoing upper airway viral shedding in outpatients with uncomplicated COVID-19. Diagn. Microbiol. Infect. Dis. 2022;102:115612. doi: 10.1016/j.diagmicrobio.2021.115612.
    1. Reiss S., Baxter A.E., Cirelli K.M., Dan J.M., Morou A., Daigneault A., Brassard N., Silvestri G., Routy J.-P., Havenar-Daughton C., et al. Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLoS One. 2017;12:e0186998. doi: 10.1371/journal.pone.0186998.
    1. Chakraborty S., Gonzalez J.C., Sievers B.L., Mallajosyula V., Chakraborty S., Dubey M., Ashraf U., Cheng B.Y.-L., Kathale N., Tran K.Q.T., et al. Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Sci. Transl. Med. 2022;14:eabm7853. doi: 10.1126/scitranslmed.abm7853.
    1. Wei J., Matthews P.C., Stoesser N., Maddox T., Lorenzi L., Studley R., Bell J.I., Newton J.N., Farrar J., Diamond I., et al. COVID-19 Infection Survey team Anti-spike antibody response to natural SARS-CoV-2 infection in the general population. Nat. Commun. 2021;12:6250. doi: 10.1038/s41467-021-26479-2.
    1. Hu Z., van der Ploeg K., Chakraborty S., Arunachalam P., Mori D.M., Jacobson K.B., Bonilla H., Parsonnet J., Andrews J., Hedlin H., et al. Early immune responses have long-term associations with clinical, virologic, and immunologic outcomes in patients with COVID-19. medRxiv. 2021 doi: 10.1101/2021.08.27.21262687. Preprint at.
    1. Menten P., Proost P., Struyf S., Van Coillie E., Put W., Lenaerts J.-P., Conings R., Jaspar J.-M., De Groote D., Billiau A., et al. Differential induction of monocyte chemotactic protein-3 in mononuclear leukocytes and fibroblasts by interferon-α/β and interferon-γ reveals MCP-3 heterogeneity. Eur. J. Immunol. 1999;29:678–685. doi: 10.1002/(sici)1521-4141(199902)29:02<678::aid-immu678>;2-j.
    1. Proost P., Wuyts A., van Damme J. Human monocyte chemotactic proteins-2 and -3: structural and functional comparison with MCP-1. J. Leukoc. Biol. 1996;59:67–74. doi: 10.1002/jlb.59.1.67.
    1. Merad M., Martin J.C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat. Rev. Immunol. 2020;20:355–362. doi: 10.1038/s41577-020-0331-4.
    1. Yang Y., Shen C., Li J., Yuan J., Wei J., Huang F., Wang F., Li G., Li Y., Xing L., et al. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J. Allergy Clin. Immunol. 2020;146:119–127.e4. doi: 10.1016/j.jaci.2020.04.027.
    1. Mateus J., Dan J.M., Zhang Z., Rydyznski Moderbacher C., Lammers M., Goodwin B., Sette A., Crotty S., Weiskopf D. Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells. Science. 2021;374:eabj9853. doi: 10.1126/science.abj9853.
    1. Mulligan M.J., Lyke K.E., Kitchin N., Absalon J., Gurtman A., Lockhart S., Neuzil K., Raabe V., Bailey R., Swanson K.A., et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020;586:589–593. doi: 10.1038/s41586-020-2639-4.
    1. Sahin U., Muik A., Derhovanessian E., Vogler I., Kranz L.M., Vormehr M., Baum A., Pascal K., Quandt J., Maurus D., et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020;586:594–599. doi: 10.1038/s41586-020-2814-7.
    1. Woldemeskel B.A., Garliss C.C., Blankson J.N. SARS-CoV-2 mRNA vaccines induce broad CD4+ T cell responses that recognize SARS-CoV-2 variants and HCoV-NL63. J. Clin. Invest. 2021;131:e149335. doi: 10.1172/jci149335.
    1. Betts M.R., Nason M.C., West S.M., De Rosa S.C., Migueles S.A., Abraham J., Lederman M.M., Benito J.M., Goepfert P.A., Connors M., et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006;107:4781–4789. doi: 10.1182/blood-2005-12-4818.
    1. Lin L., Finak G., Ushey K., Seshadri C., Hawn T.R., Frahm N., Scriba T.J., Mahomed H., Hanekom W., Bart P.-A., et al. COMPASS identifies T-cell subsets correlated with clinical outcomes. Nat. Biotechnol. 2015;33:610–616. doi: 10.1038/nbt.3187.
    1. Murugesan K., Jagannathan P., Pham T.D., Pandey S., Bonilla H.F., Jacobson K., Parsonnet J., Andrews J.R., Weiskopf D., Sette A., et al. Interferon-γ release assay for accurate detection of severe acute respiratory syndrome coronavirus 2 T-cell response. Clin. Infect. Dis. 2021;73:e3130–e3132. doi: 10.1093/cid/ciaa1537.
    1. Tan A.T., Lim J.M.E., Le Bert N., Bert N.L., Kunasegaran K., Chia A., Qui M.D.C., Tan N., Chia W.N., de Alwis R., et al. Rapid measurement of SARS-CoV-2 spike T cells in whole blood from vaccinated and naturally infected individuals. J. Clin. Invest. 2021;131 doi: 10.1172/jci152379.
    1. Lönnberg T., Svensson V., James K.R., Fernandez-Ruiz D., Sebina I., Montandon R., Soon M.S.F., Fogg L.G., Nair A.S., Liligeto U.N., et al. Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves T H 1/T FH fate bifurcation in malaria. Sci. Immunol. 2017;2:eaal2192. doi: 10.1126/sciimmunol.aal2192.
    1. Jagannathan P., Eccles-James I., Bowen K., Nankya F., Auma A., Wamala S., Ebusu C., Muhindo M.K., Arinaitwe E., Briggs J., et al. IFNγ/IL-10 Co-producing cells dominate the CD4 response to malaria in highly exposed children. PLoS Pathog. 2014;10:e1003864. doi: 10.1371/journal.ppat.1003864.
    1. Ni L., Ye F., Cheng M.-L., Feng Y., Deng Y.-Q., Zhao H., Wei P., Ge J., Gou M., Li X., et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity. 2020;52:971–977.e3. doi: 10.1016/j.immuni.2020.04.023.
    1. Arunachalam P.S., Scott M.K.D., Hagan T., Li C., Feng Y., Wimmers F., Grigoryan L., Trisal M., Edara V.V., Lai L., et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature. 2021;596:410–416. doi: 10.1038/s41586-021-03791-x.
    1. Keeton R., Tincho M.B., Ngomti A., Baguma R., Benede N., Suzuki A., Khan K., Cele S., Bernstein M., Karim F., et al. T cell responses to SARS-CoV-2 spike cross-recognize Omicron. Nature. 2022;603:488–492. doi: 10.1038/s41586-022-04460-3.
    1. Tarke A., Coelho C.H., Zhang Z., Dan J.M., Yu E.D., Methot N., Bloom N.I., Goodwin B., Phillips E., Mallal S., et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell. 2022;185:847–859.e11. doi: 10.1016/j.cell.2022.01.015.
    1. Bray N.L., Pimentel H., Melsted P., Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 2016;34:525–527. doi: 10.1038/nbt.3519.
    1. Korotkevich G., Sukhov V., Budin N., Shpak B., Artyomov M.N., Sergushichev A. Fast gene set enrichment analysis. bioRxiv. 2021 doi: 10.1101/060012. Preprint at.
    1. Roederer M., Nozzi J.L., Nason M.C. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytometry A. 2011;79:167–174. doi: 10.1002/cyto.a.21015.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere