Maintenance of memory lymphocytes in protective and auto-reactive immunological memory
The focus of our research is detailing out the new concept of the organization of immunological memory in the bone marrow with the aim to identify novel molecular targets for the ablation of pathogenic immunological memory cells.
Memory T helper (Th) cells and long-lived ‘memory’ plasma cells are critical for long-lasting immunological memory to pathogens and autoantigens. Despite their central role, the generation and maintenance of memory Th cells and memory plasma cells in the body has remained unclear. In our group, we have characterized the microenvironment ‘niches’ for survival of memory Th cells and memory plasma cells in the bone marrow (BM). CD69, integrin α2 (CD49b), integrin β1 (CD29) and CXCR4 are required as receptors for the generation and maintenance of memory Th cells and memory plasma cells in the BM. These molecules can be used as therapeutic target molecules to block the generation and maintenance of pathogenic memory Th cells and memory plasma cells in autoimmune diseases. The major research interest in our group is to understand how memory Th cells and memory plasma cells are generated and maintained in infectious and autoimmune diseases.
Recently, we have shown that Salmonella (S.) Typhimurium specifically reduces the numbers of IgG-secreting plasma cells in the BM thereby preventing the generation of an efficient humoral memory response against it. The Salmonella-secreted protein SiiE plays a major role in this process as attenuated SiiE-deficient S. Typhimurium induces high and lasting titers of specific and protective S. Typhimurium-specific IgG and qualifies as an efficient vaccine against S. Typhimurium. A SiiE-derived peptide with homology to laminin β1 is sufficient to ablate IgG-secreting plasma cells from the BM, interacting with a laminin receptor, integrin β1, in competition with laminin β1. Laminin β1 is also defined as a component of niches specific for IgG-secreting plasma cells in the BM. It therefore might qualify as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma. In addition, this is a potentially vital clinical finding as it points to the fact that S. Typhimurium may cancel humoral immune memory which has been already generated by vaccination.
Immunological memory, Memory T helper cells, Long-lived plasma cells, Bone marrow, Stromal niches
Koji Tokoyoda, PhD
Shintaro Hojyo, PhD
Prof. Dr. Stefan H.E. Kaufmann, Max Planck Institute for Infection Biology, Immunology, Berlin, Germany
Prof. Dr. Toshinori Nakayama, Chiba University, Graduate School of Medicine, Immunology, Chiba, Japan
Prof. Dr. Tomoko Yamamoto, Dr. Akiko Takaya, Graduate School and Faculty of Pharmaceutical Sciences, Chiba University, Microbiology, Chiba, Japan
- 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. Natl. Acad. Sci. USA 116(15):7425-7430.
- Chang HD, Tokoyoda K, Radbruch A. (2018) Immunological memories of the bone marrow. Rev. 283(1):86-98.
- 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. Natl. Acad. Sci. USA 115(6):1334-1339.
- 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)