Tracing the secrets of longevity of 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.
Immunological memory, T helper lymphocytes, Plasma cells, Bone marrow, Stromal niches, Salmonella
Koji Tokoyoda, PhD
Shintaro Hojyo, PhD
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
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 116(15):7425-7430.
2. Sarkander J, Hojyo S, Tokoyoda K. (2016) Vaccination to gain humoral immune memory. Clin. Transl. Immunology 5(12):e120.
3. 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 Immunol 1:eaaf9154.
4. 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.
5. Hanazawa A, Löhning M, Radbruch A, and Tokoyoda K. (2013) CD49b/CD69-dependent generation of resting T helper cell memory. Front. Immunol. 4:183.
6. 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.
7. 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.
8. 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.
9. Tokoyoda K, Hauser AE, Nakayama T, Radbruch A. Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10:193-200, 2010.
10. Tokoyoda K, Zehentmeier S, Radbruch A. Organisation and maintenance of immunological memory by stroma niches. Eur. J. Immunol. 39:2095-2099, 2009.
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.
- Leibniz Association (International Leibniz Research Cluster ‘ImmunoMemory’).
- Deutsche Forschungsgemeinschaft (DFG) TO944/2-1, TO944/3-1
- Alexander von Humboldt Foundation (Fellowship for Postdoc, Shintaro Hojyo)
- Japan Society for the Promotion of Science (JSPS Overseas Research Fellowships, Shintaro Hojyo)