Tracing the secrets of longevity in protective and pathogenic memory lymphocytes



Memory T helper cells and memory plasma cells are critical for long-lasting humoral immune memory to infectious pathogens and autoantigens. Despite their central role, how the memory cells are generated and maintained in the body still remains unclear. We aim at understanding the dynamics of memory T helper cells and memory plasma cells during immune response(s) and the mechanisms of their survival on a molecular level.

Recently, we have found and further described the microenvironment ‘niches’ for survival of memory T helper cells and memory plasma cells. Memory T helper cells and memory plasma cells reside in IL-7+collagen-XI+ and CXCL12+ stromal cells of the bone marrow, respectively. Although it had been commonly thought that memory T helper cells are circulating and need the presence of antigen, our results show that protective memory T helper cells are not circulating and instead reside and rest in the bone marrow in an antigen-independent manner. We have also reported that CD49b (integrin alpha2), CD69 (a C-type lectin) and Myosin light chain 9/12 (a ligand of CD69) are required for the generation and maintenance of protective memory T helper cells in the bone marrow and that CD49b+T-bet/CXCR3+ activated CD4 T cells generated during the primary immune response are the precursors of memory T helper cells in the bone marrow. Most recently we could describe an unexpected mechanism by which Salmonella regulate IgG-secreting memory plasma cells in the bone marrow.

The detailed knowledge of the molecules and signals involved in the maintenance of memory cells is crucial for the development of new therapies specifically targeting these cells in autoimmune diseases.

Selected Publications

  1. Sarkander J, Hojyo S, Tokoyoda K. (2016) Vaccination to gain humoral immune memory. Clin. Transl. Immunology 5(12):e120.
  2. 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. Science Immunolology 1:eaaf9154.
  3. 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.
  4. Hanazawa A, Löhning M, Radbruch A, and Tokoyoda K. (2013) CD49b/CD69-dependent generation of resting T helper cell memory. Front. Immunol. 4:183.
  5. 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.
  6. 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. USA109:7409-7414, 2012.
  7. Tokoyoda K, Radbruch A.Signals controlling rest and reactivation of T helper memory lymphocytes in bone marrow.Cell. Mol. Life Sci. 69:1609-1613, 2012.
  8. Tokoyoda K, Hauser AE, Nakayama T, Radbruch A. Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10:193-200, 2010.
  9. Tokoyoda K, Zehentmeier S, Radbruch A. Organisation and maintenance of immunological memory by stroma niches. Eur. J. Immunol. 39:2095-2099, 2009.
  10. 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.
  11. 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:
Koji Tokoyoda, PhD

Shintaro Hojyo, PhD

PhD students:
Jana Sarkander
Mathias Mursell
Tsung-Yen Wu

Yuzuru Yamasaki

Cooperation partners

  • NIH, NIAID, Bethesda, MD, USA: Dr. Jinfang Zhu

  • MPI for Infection Biology, Berlin: Prof. Dr. Stefan H.E. Kaufmann

  • University of Cologne, Cologne: Prof. Dr. Beate Eckes

  • Chiba University, Chiba, Japan: Prof. Dr. Toshinori Nakayama

  • Chiba University, Chiba, Japan: Prof. Dr. Tomoko Yamamoto, Dr. Akiko Takaya

  • RIKEN, Yokohama, Japan: Prof. Dr. Masato Kubo

  • IFReC, Osaka University, Osaka, Japan: Prof. Dr. Takashi Nagasawa

  • Kyoto University, Kyoto, Japan: Prof. Dr. Koichi Ikuta

  • DRFZ, Berlin: Prof. Dr. A. Radbruch, Prof. Dr. Max Löhning, Prof. Dr. Anja E. Hauser, Prof. Dr. Andreas Hutloff, Prof. Alf Hamann, Prof. Dr. Falk Hiepe

Dr. Koji Tokoyoda

Deutsches Rheuma-Forschungszentrum Berlin
Charitéplatz 1
10117 Berlin, Germany

Phone+49 (0)30 28460-782
Fax+49 (0)30 28460-604

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

Radbruch Prof. Dr. rer. nat. Andreas Radbruch Cell Biology Triantafyllopoulou_klein Dr. Antigoni Triantafyllopoulou Innate Immunity in Rheumatic Diseases Thurley Dr. Kevin Thurley Systems Biology of inflammation Ahmed Hegazy Dr. med. Dr. rer. nat. Ahmed N. Hegazy Inflammatory Mechanisms Polansky Dr. Julia Polansky-Biskup Immuno-Epigenetics Melchers Prof. Dr. Fritz Melchers Lymphocyte Development Farzin Mashreghi Dr. Mir-Farzin Mashreghi Therapeutic Gene Regulation Kruglov Dr. rer. nat. Andrey Kruglov Chronic Inflammation Loehning Prof. Dr. Max Löhning Pitzer Lab Osteoarthritis Research Kubagawa Prof. Dr. Hiromi Kubagawa Humoral Immune Regulation Hauser Prof. Dr. med. vet. Anja Erika Hauser Immune Dynamics Tokoyoda Dr. Koji Tokoyoda Osteoimmunology Scheffold Prof. Dr. rer. nat. Alexander Scheffold Cellular Immunology Niesner Dr. rer. nat. Raluca Niesner Biophysical Analytics Strangfeld Dr. med. Anja Strangfeld Pharmacoepidemiology Minden Prof. Dr. med. Kirsten Minden Paediatric Rheumatology Listing Dr. Joachim Listing Statistics & Clinical Studies Angela_Zink_230x230 Prof. Dr. Angela Zink Health Services Research Worm Prof. Dr. med. Margitta Worm Allergology Poddubnyy Prof. Dr. Denis Poddubnyy Spondyloarthritides Riemekasten Prof. Dr. med. Gabriela Riemekasten Cell Autoimmunity Hiepe Prof. Dr. med. Falk Hiepe Autoimmunology Hamann Prof. Dr. rer. nat. Alf Hamann Experimental Rheumatology Doerner Prof. Dr. med. Thomas Dörner B Cell Memory Buttgereit Prof. Dr. med. Frank Buttgereit Glucocorticoids & Bioenergetics Romagnani Prof. Dr. Chiara Romagnani Innate Immunity Hutloff Dr. rer. nat. Andreas Hutloff Chronic Immune Reactions Fillatreau Prof. Dr. rer. nat. Simon Fillatreau Immune Regulation Baumgrass Prof. Dr. Ria Baumgrass Signal Transduction Nedospasow Prof. Dr. Sergei Nedospasov Inflammation Biology