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  • 제25권2호
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  • Pages.4.1-4.12
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  • 2025
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Patients With Mild COVID-19 Exhibit Low Functional Avidity of SARS-CoV-2 Membrane Protein-Reactive CD4+ T Cells

  • A-Reum Kim (The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS)) ;
  • June-Young Koh (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Min-Seok Rha (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Jae Hyung Jung (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Jae-Hoon Ko (Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Hee Kyoung Choi (Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine) ;
  • Ji Hoon Jeon (Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine) ;
  • Hyeri Seok (Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine) ;
  • Dae Won Park (Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine) ;
  • Kyong Ran Peck (Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Jun Yong Choi (Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine) ;
  • Su-Hyung Park (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Won Suk Choi (Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine) ;
  • Hye Won Jeong (Department of Internal Medicine, Chungbuk National University College of Medicine) ;
  • Eui-Cheol Shin (The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS))
  • 투고 : 2024.08.09
  • 심사 : 2025.01.06
  • 발행 : 2025.04.30
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초록

Herein, we found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-unexposed individuals exhibited an increased frequency of CD4+ T cells against SARS-CoV-2 membrane (M) protein, suggesting that SARS-CoV-2 M-reactive cells may be primed by previous infection with common cold coronaviruses (CCCoVs). We confirmed that CCCoV M-reactive CD4+ T cells cross-recognize SARS-CoV-2 M in unexposed individuals. Among coronavirus disease 2019 (COVID-19) convalescents and unexposed individuals, SARS-CoV-2 M-reactive CD4+ T cells exhibited significantly lower functional avidity than CD4+ T cells reactive to other viruses. Importantly, convalescents from mild COVID-19 had SARS-CoV-2 M-reactive CD4+ T cells with significantly lower functional avidity than convalescents from severe COVID-19. The current data suggest that pre-existing CCCoV M-specific memory CD4+ T cells may contribute to controlling SARS-CoV-2 infection by cross-reactivity, leading to mild disease but leaving memory cells with low functional avidity to SARS-CoV-2 M due to incomplete homology. These data provide indirect evidence that pre-existing cross-reactive CD4+ T cells contribute to protection from severe COVID-19.

키워드

과제정보

This work was supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2024-00439160 and RS-2023-00222762) and by the Institute for Basic Science (IBS), Republic of Korea (IBS-R801-D2).

참고문헌

  1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
  2. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-273. https://doi.org/10.1038/s41586-020-2012-7
  3. Weiskopf D, Schmitz KS, Raadsen MP, Grifoni A, Okba NMA, Endeman H, van den Akker JPC, Molenkamp R, Koopmans MPG, van Gorp ECM, 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. https://doi.org/10.1126/sciimmunol.abd2071
  4. Sekine T, Perez-Potti A, Rivera-Ballesteros O, Strålin K, Gorin JB, 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.e14. https://doi.org/10.1016/j.cell.2020.08.017
  5. Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Weiskopf D, Belanger S, Abbott RK, 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. https://doi.org/10.1016/j.cell.2020.09.038
  6. Jung JH, Rha MS, Sa M, Choi HK, Jeon JH, Seok H, Park DW, Park SH, Jeong HW, Choi WS, et al. 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. https://doi.org/10.1038/s41467-021-24377-1
  7. Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, Rawlings SA, Sutherland A, Premkumar L, Jadi RS, 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.e15. https://doi.org/10.1016/j.cell.2020.05.015
  8. Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng MHY, Lin M, Tan N, Linster M, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020;584:457-462. https://doi.org/10.1038/s41586-020-2550-z
  9. Mateus J, Grifoni A, Tarke A, Sidney J, Ramirez SI, Dan JM, Burger ZC, Rawlings SA, Smith DM, Phillips E, et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 2020;370:89-94. https://doi.org/10.1126/science.abd3871
  10. Nelde A, Bilich T, Heitmann JS, Maringer Y, Salih HR, Roerden M, Lubke M, Bauer J, Rieth J, Wacker M, et al. SARS-CoV2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nat Immuno1 2021;22:74-85. https://doi.org/10.1038/s41590-020-00808-x
  11. Peng Y, Mentzer AJ, 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. https://doi.org/10.1038/s41590-020-0782-6
  12. Thieme CJ, Anft M, Paniskaki K, Blazquez-Navarro A, Doevelaar A, Seibert FS, Hoelzer B, Konik MJ, Berger MM, Brenner T, et al. Robust T cell response toward spike, membrane, and nucleocapsid SARS-CoV-2 proteins is not associated with recovery in critical COVID-19 patients. Cell Rep Med 20201:100092. https://doi.org/10.1016/j.xcrm.2020.100092
  13. Reynolds CJ, Swadling L, Gibbons JM, Pade C, Jensen MP, Diniz MO, Schmidt NM, Butler DK, Amin OE, Bailey SNL, et al. Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection. Sci Immunol 2020;5.eabf3698. https://doi.org/10.1126/sciimmunol.abf3698
  14. Low JS, Vaqueirinho D, Mele F, Foglierini M, Jerak J, Perotti M, Jarrossay D, Jovic S, Perez L, Cacciatore R, et al. Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2. Science 2021;372:1336-1341. https://doi.org/10.1126/science.abg8985
  15. Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, Hippenstiel S, Dingeldey M, Kruse B, Fauchere F, et al. SARS-CoV2-reactive T cells in healthy donors and patients with COVID-19. Nature 2020;587:270-274. https://doi.org/10.1038/s41586-020-2598-9
  16. Schulien I, Kemming], Oberhardt V, Wild K, Seidel LM, Killmer S, Sagar Daul F, Salvat Lago M, Decker A, et al. Characterization of pre-existing and induced SARS-CoV2-specific CD8+ T cells. Nat Med 2021:27:78-85. https://doi.org/10.1038/s41591-020-01143-2
  17. Mallajosyula V, Ganjavi C, Chakraborty S, McSween AM, Pavlovitch-Bedzyk AJ, Wilhelmy], Nau A, Manohar M, Nadeau KC, Davis MM. CD8+ T cells specific for conserved coronavirus epitopes correlate with milder disease in COVID-19 patients. Sci Immunol 2021;6:eabg5669. https://doi.org/10.1126/sciimmunol.abg5669
  18. Swadling L, Diniz MO, Schmidt NM, Amin OE, Chandran A, Shaw E, Pade C, Gibbons JM, Le Bert N, Tan AT, et al. Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2. Nature 2022;601:110-117. https://doi.org/10.1038/s41586-021-04186-8
  19. Loyal L, Braun J, Henze L, Kruse B, Dingeldey M, Reimer U, Kern F, Schwarz T, Mangold M, Unger C, et al. Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination. Science 2021:374:2abh1823. https://doi.org/10.1126/science.abh1823
  20. Murray SM, Ansari AM, Frater], Klenerman P, Dunachie S, Barnes E, Ogbe A. The impact of pre-existing cross-reactive immunity on SARS-CoV2 infection and vaccine responses. Nat Reu Immunol 2023;23:304-316. https://doi.org/10.1038/s41577-022-00809-x
  21. Kundu R, Narean JS, Wang L, Fenn J, Pillay T, Fernandez ND, Conibear E, Koycheva A, Davies M, Tolosa-Wright M, et al. Cross-reactive memory T cells associate with protection against SARS-CoV2 infection in COVID-19 contacts. Nat Commun 2022:13:80. https://doi.org/10.1038/s41467-021-27674-x
  22. Sagar M, Reifler K, Rossi M, Miller NS, Sinha P, White LF, Mizgerd JP. Recent endemic coronavirus infection is associated with less-severe COVID-19. J Clin Invest 2021:131:143380. https://doi.org/10.1172/JCI143380
  23. Bertoletti A, Tan AT, Le Bert N. The T-cell response to SARS-CoV-2: kinetic and quantitative aspects and the case for their protective role. Oxf Open Immunol 2021;2:iqab006. https://doi.org/10.1093/oxfimm/iqab006
  24. National Institutes of Health, COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Bethesda, MD: National Institutes of Health; 2020.
  25. Vigano S, Utzschneider DT, Perreau M, Pantaleo G, Zehn D, Harari A. Functional avidity: a measure to predict the efficacy of effect or T cells? Clin Deu Immunol 2012;2012:153863. PUBMEDll https://doi.org/10.1155/2012/153863
  26. Clutton GT, Weideman AMK, Mischell MA, Kallon S, Conrad SZ, Shaw FR, Warren JA, Lin L, Kuruc JD, Xu Y, et al. CD3 downregulation identifies high-avidity human CD8 T cells. Clin Exp Immunol 2024;215:279-290. PUBMED I https://doi.org/10.1093/cei/uxad124
  27. Bacher P, Rosati E, Esser D, Martini GR, Saggau C, Schiminsky E, Dargvainiene 1, Schroder I, Wieters I, Khodamoradi Y et al. Low-avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19. Immunity 2020;53:1258-1271.e5. https://doi.org/10.1016/j.immuni.2020.11.016