Tokoyoda lab

Maintenance of memory lymphocytes in protective and auto-reactive immunological memory

Introduction
Members
Cooperation partners
Selected Publications
Third party funding projects

Osteoimmunology

Memory T helper (Th) cells are critical for long-lasting immune memory to infectious pathogens and autoantigens. Despite their central role, the generation, maintenance and reactivation of memory Th cells in the body still remained unclear. Recently, we have found and further described the microenvironment ‘niches’ for survival of memory Th cells in the bone marrow (BM). We have also reported that CD69 and integrin alpha2 (CD49b) are required as homing receptors for the generation and maintenance of memory Th cells in the BM. These molecules can be target molecules to block the generation and maintenance of pathogenic memory Th cells in autoimmune diseases.

We have identified the precursors of BM memory Th cells as CD49b+T-bet+ CD4 T cells generated during the primary immune response. It has been previously reported that B cells contribute to the generation of effector Th cells (follicular helper T cells). However, we determined that the generation of the precursors of BM memory Th cells was negatively controlled by B cells. These findings suggest that B cells play a role in the bifurcation of activated effector and resting memory Th cell lineages. This finding alerts that, if only inflammation is blocked, pathogenic memory can be inversely enhanced. We should consider blocking both effector and memory to treat autoimmune diseases.

We have identified a novel functional ligand of CD69, myosin light chain (Myl) 9 and 12. Myl9/12 is expressed in megakaryocytes and platelets. The migratory precursors of BM memory Th cells adhere to BM sinusoidal endothelial cells via the interaction of CD69 and Myl9/12. In the pathogenesis of allergic airway inflammation, the interaction functions to recruit inflammatory T cells into inflamed tissues. The role of the interaction of CD69 and Myl9/12 in rheumatic diseases will be investigated.

In our most recent studies, we also succeeded in describing a previously unknown and surprising mechanism by which Salmonella regulates the antibody IgG-secreting memory plasma cells in the bone marrow.

Group Leader
    Dr. Koji Tokoyoda

Dr. Koji Tokoyoda

Deutsches Rheuma-Forschungszentrum Berlin
Osteoimmunology
Charitéplatz 1
10117 Berlin, Germany

Phone+49 (0)30 28460-782
Fax+49 (0)30 28460-604
tokoyoda@drfz.de

Keywords
Immunological memory, T helper lymphocytes, Plasma cells, Bone marrow, Stromal niches, Salmonella

Continue to Members

Group leader
Koji Tokoyoda, PhD

Scientists
Shintaro Hojyo, PhD

PhD students
Jana Sarkander
Mathias Mursell
Tsung-Yen Wu

Students
Yuzuru Yamasaki

Group Leader
    Dr. Koji Tokoyoda

Dr. Koji Tokoyoda

Deutsches Rheuma-Forschungszentrum Berlin
Osteoimmunology
Charitéplatz 1
10117 Berlin, Germany

Phone+49 (0)30 28460-782
Fax+49 (0)30 28460-604
tokoyoda@drfz.de

Keywords
Immunological memory, T helper lymphocytes, Plasma cells, Bone marrow, Stromal niches, Salmonella

Continue to Cooperation partners
  1. Dr. Stefan H.E. Kaufmann, Max Planck Institute for Infection Biology, Immunology, Berlin, Germany
  2. Dr. Toshinori Nakayama, Immunology, Chiba University, Chiba, Japan
  3. Dr. Tomoko Yamamoto, Dr. Akiko Takaya, Microbiology, Chiba University, Chiba, Japan
Group Leader
    Dr. Koji Tokoyoda

Dr. Koji Tokoyoda

Deutsches Rheuma-Forschungszentrum Berlin
Osteoimmunology
Charitéplatz 1
10117 Berlin, Germany

Phone+49 (0)30 28460-782
Fax+49 (0)30 28460-604
tokoyoda@drfz.de

Keywords
Immunological memory, T helper lymphocytes, Plasma cells, Bone marrow, Stromal niches, Salmonella

Continue to Selected Publications
  1. Männe C*, Takaya A* (*equally contributed), Yamasaki Y, Mursell M, Hojyo S, Wu T-Y, Sarkander J, McGrath MA, Cornelis R, Hahne S, Cheng Q, Kawamoto T, Hiepe F, Kaufmann SHE, Yamamoto T, Radbruch A, Tokoyoda K. (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 in press.
  2. Chang HD, Tokoyoda K, Radbruch A. (2018) Immunological memories of the bone marrow. Immunol. Rev. 283(1):86-98.
  3. Siracusa F, McGrath MA, Maschmeyer P, Bardua M, Lehmann K, Heinz G, Durek P, Heinrich FF, Mashreghi MF, Chang HD, Tokoyoda K, Radbruch A. (2018) Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc. Natl. Acad. Sci. USA 115(6):1334-1339.
  4. Sarkander J, Hojyo S, Tokoyoda K. (2016) Vaccination to gain humoral immune memory. Clin. Transl. Immunol. 5(12):e120.
  5. Hayashizaki K*, Kimura MY*, Tokoyoda K* (*equally contributed) 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. (2016) Myosin light chain 9 and 12 are functional ligands for CD69 that regulate airway inflammation. Sci. Immunol. 1:eaaf9154.
  6. Hojyo S, Sarkander J, Männe C, Mursell M, Hanazawa A, Zimmel D, Zhu J, Paul WE, Fillatreau S, Löhning M, Radbruch A, Tokoyoda K. (2016) B cells negatively regulate the establishment of CD49b+T-bet+ resting memory T helper cells in the bone marrow. Front. Immunol. 7:26.
  7. Hanazawa A, Löhning M, Radbruch A, and Tokoyoda K. (2013) CD49b/CD69-dependent generation of resting T helper cell memory. Front. Immunol. 4:183.
  8. Hanazawa A, Hayashizaki K, Shinoda K, Yagita H, Okumura K, Löhning M, Hara T, Tani-ichi S, Ikuta K, Eckes B, Radbruch A, Tokoyoda K* and Nakayama T* (*equally contributed). (2013) CD49b-dependent establishment of T helper cell memory. Immunol. Cell Biol. 91:524-531.
  9. Shinoda K*, Tokoyoda K* (* equally contributed), Hanazawa A, Hayashizaki K, Zehentmeier S, Hosokawa H, Iwamura C, Koseki H, Tumes DJ, Radbruch A, Nakayama T. Type II membrane protein CD69 regulates the formation of resting T-helper memory. Proc. Natl. Acad. Sci. USA 109:7409-7414, 2012.
  10. Tokoyoda K, Hauser AE, Nakayama T, Radbruch A. Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10:193-200, 2010.
  11.  Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grün JR, Löhning M, Radbruch A. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30:721-730, 2009.
  12. Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20:707-718, 2004.
Group Leader
    Dr. Koji Tokoyoda

Dr. Koji Tokoyoda

Deutsches Rheuma-Forschungszentrum Berlin
Osteoimmunology
Charitéplatz 1
10117 Berlin, Germany

Phone+49 (0)30 28460-782
Fax+49 (0)30 28460-604
tokoyoda@drfz.de

Keywords
Immunological memory, T helper lymphocytes, Plasma cells, Bone marrow, Stromal niches, Salmonella

Continue to Third party funding projects
  1. Leibniz Association (International Leibniz Research Cluster ‘ImmunoMemory’).
  2. Deutsche Forschungsgemeinschaft (DFG) TO944/2-1, TO944/3-1
  3. Alexander von Humboldt Foundation (Fellowship for Postdoc, Shintaro Hojyo)
  4. Japan Society for the Promotion of Science (JSPS Overseas Research Fellowships, Shintaro Hojyo)
Group Leader
    Dr. Koji Tokoyoda

Dr. Koji Tokoyoda

Deutsches Rheuma-Forschungszentrum Berlin
Osteoimmunology
Charitéplatz 1
10117 Berlin, Germany

Phone+49 (0)30 28460-782
Fax+49 (0)30 28460-604
tokoyoda@drfz.de

Keywords
Immunological memory, T helper lymphocytes, Plasma cells, Bone marrow, Stromal niches, Salmonella

Continue to Introduction