Identifizierung Antigen-präsentierender Zellen für Gedächtnis-T-Helfer-Lymphozyten in der sekundären Immunantwort
Zusammenfassung der Projektergebnisse
Memory Th cells are essential for long-lasting immunity and effective secondary immune responses against previously encountered antigens. However, it remains unknown whether memory Th cells can be reactivated without re-invasion of pathogens or antigens in vivo. A B cell-depleting agent, anti-CD20 antibody, clinically known as Rituximab, was used to investigate the role of B cells in the maintenance and reactivation of memory Th cells. By means of an adoptive transfer model that generates mice harboring antigen-specific memory Th cells, we found that an injection of anti-CD20 but not anti-IgD/M expanded the number of antigen-specific memory Th cells in the spleen. Further analyses showed that the expansion of antigen-specific memory Th cells was dynamically caused by the presentation of antigens remaining in necrotic B cells within 33 days after immunization. Instead of necrotic B cells by anti-CD20, Toll-like receptor 9 agonists, e.g., CpG, together with anti-IgD also induced the expansion of antigen-specific memory Th cells. In addition, we showed that mature B cells are a reservoir of antigens for a certain period of time (33 days, but not 73 days) after immunization. These data suggest that in the case of B cell damages by clinical treatment of anti-CD20, Rituximab and some infections, splenic antigen-specific memory Th cells can be expanded without re-invasion of pathogen. Thus, we alarm that Rituximab for patients with autoimmune diseases may expand auto-reactive memory Th cells and enhance the potential and magnitude of the relapse. In this project, we would identify APCs for memory Th cells in secondary immune response. First, we investigated a role of B cells in secondary immune response by injection of anti-CD20. However, surprisingly, followed by antigen challenge, memory Th cells were expanded. We had doubt on the unexpected result and tried to clarify the reason. The research on identification of APCs for memory Th cells now continues in our lab. However, this switched project found an unexpected phenomenon and clarified a novel cellular and molecular mechanism.
Projektbezogene Publikationen (Auswahl)
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(2017) Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in the pathogenesis of airway inflammation. Immunol Rev 278:87-100
Kimura MY, Hayashizaki K, Tokoyoda K, Takamura S, Motohashi S, Nakayama T
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(2017) Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation. Eur J Immunol 47:1900-1905
Siracusa F, Alp ÖS, Maschmeyer P, McGrath M, Mashreghi MF, Hojyo S, Chang HD, Tokoyoda K, Radbruch A
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(2018) Immunological memories of the bone marrow. Immunol Rev 283:86-98
Chang HD, Tokoyoda K, Radbruch A
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(2018) Multiplexed fluorescence microscopy reveals heterogeneity among stromal cells in mouse bone marrow sections. Cytometry A 93:876-888
Holzwarth K, Köhler R, Philipsen L, Tokoyoda K, Ladyhina V, Wählby C, Niesner RA, Hauser AE
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(2018) Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc Natl Acad Sci USA 115:1334-1339
Siracusa F, McGrath MA, Maschmeyer P, Bardua M, Lehmann K, Heinz G, Durek P, Heinrich FF, Mashreghi MF, Chang HD, Tokoyoda K, Radbruch A
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(2019) Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology. J Allergy Clin Immunol 144:549- 560.e10
Tumes D, Hirahara K, Papadopoulos M, Shinoda K, Onodera A, Kumagai J, Yip KH, Pant H, Kokubo K, Kiuchi M, Aoki A, Obata-Ninomiya K, Tokoyoda K, Endo Y, Kimura MY, Nakayama T
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(2019) Pathogenic memory plasma cells in autoimmunity. Curr Opin Immunol 61:86-91
Chang HD, Tokoyoda K, Hoyer B, Alexander T, Khodadadi L, Mei H, Dörner T, Hiepe F, Burmester GR, Radbruch A
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(2019) Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow. Proc Natl Acad Sci USA 116:7425-7430
Männe C, Takaya A, Yamasaki Y, Mursell M, Hojyo S, Wu TY, Sarkander J, McGrath MA, Cornelis R, Hahne S, Cheng Q, Kawamoto T, Hiepe F, Kaufmann SHE, Yamamoto T, Radbruch A, Tokoyoda K
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(2020) Enhanced cell division is required for the generation of memory CD4 T cells to home to their proper location. Front Immunol 10:3113
Sarkander J, Hojyo S, Mursell M, Yamasaki Y, Wu TY, Tumes DT, Miyauchi K, Tran CT, Zhu J, Löhning M, Hutloff A, Mashreghi MF, Kubo M, Radbruch A, Tokoyoda K
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(2020) Humoral immunity versus Salmonella. Front Immunol 10:3155
Takaya A, Yamamoto T, Tokoyoda K
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(2020) Multiple developmental pathways lead to the generation of CD4 T-cell memory. Int Immunol 32:589-595
Hojyo S, Tumes D, Murata A, Tokoyoda K
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(2020) Stromal cell-contact dependent PI3K and APRIL induced NF-κB signaling prevent mitochondrial- and ER stress induced death of memory plasma cells. Cell Rep 32:107982
Cornelis R, Hahne S, Taddeo A, Petkau G, Malko D, Durek P, Thiem M, Heiberger L, Peter L, Mohr E, Klaeden C, Tokoyoda K, Siracusa F, Hoyer BF, Hiepe F, Mashreghi MF, Melchers F, Chang HD, Radbruch A
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(2021) Homeostasis and durability of T-cell memory- The resting and the restless T-cell memory. Cold Spring Harb Perspect Biol 13:a038083
Radbruch A, McGrath MA, Siracusa F, Hoffmann U, Sercan-Alp Ö, Hutloff A, Tokoyoda K, Chang HD, Dong J
