Molekulare Charakterisierung der Überlebens-Nischen für Gedächtnis T-Helferzellen im Knochenmark
Zusammenfassung der Projektergebnisse
A depletion of activated/effector cells can suppress pathogenesis in autoimmune diseases and allergy. However, the immune disorder fails to be cured and induces the relapse. The repeated pathogenesis is provided by memory cells including memory Th cells, memory B cells and/or long-lived (memory) plasma cells. To cure autoimmune diseases, we have to deplete all memory cell populations. Memory B cells and memory plasma cells can be depleted. However, memory Th cells failed to be depleted, because it remained unclear where and how memory Th cells are maintained. Ten years ago, we showed that most memory Th cells reside and rest in the BM stromal cells (Tokoyoda et al., Immunity 2009). We then tried to determine how they are maintained in this project. We here show that splenic memory Th cells are maintained in an IL-7-dependent manner and BM memory Th cells are maintained in a CD49b-dependent manner. To deplete all memory Th cells, we have to target both types of memory Th cells. The involvement of IL-7 and CD49b was expected in the proposal. However, the finding on the role of regulatory T cells was unexpected but highly impressed. Furthermore, we found that regulatory T cells support the expression of collagens (CD49b ligand) and IL-7 in BM stromal cells. The depletion of regulatory T cells reduces the expression of collagens and IL-7 and then reduces both memory Th cells. Since memory Th cells are the main source of IL-2, a survival factor of regulatory T cells, we suggest that memory Th cells, regulatory T cells and stromal cells support each other. The project has been successfully completed according to the original proposal. It is a novel finding that resting BM memory Th cells are maintained by adhesion signal and active splenic memory Th cells are maintained by cytokine signal. Two different signals provide distinct cell status, characteristics and function. In addition, we could show a systemic cooperative mechanism among three cell populations, memory Th cells, regulatory T cells and stromal cells in the BM. These finding greatly contributes to the development of immunological memory field for basic and clinic studies.
Projektbezogene Publikationen (Auswahl)
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(2016) Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation. Sci Immunol 1:eaaf9154
Hayashizaki K, Kimura MY, Tokoyoda K, Hosokawa H, Shinoda K, Hirahara K, Ichikawa T, Onodera A, Hanazawa A, Iwamura C, Kakuta J, Muramoto K, Motohashi S, Tumes DJ, Iinuma T, Yamamoto H, Ikehara Y, Okamoto Y, Nakayama T
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(2016) Vaccination to gain humoral immune memory. Clin Transl Immunology 5:e120
Sarkander J, Hojyo S, Tokoyoda K
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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
