Memory T helper (Th) cells are critical for longlasting 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 CD49b (integrin alpha2) 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 (Tfh 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 T cells 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 most likely Myl9/12. In the pathogenesis of allergic airway inflammation, the interaction also functions to recruit inflammatory T cells into inflamed tissues. The role of the interaction of CD69 and Myl9/12 in autoimmune diseases will be investigated.
There is still much to discover about the reactivation of memory Th cells, i.e. the recall response. To determine how memory Th cells reactivate memory B cells, we currently study the cellular and molecular mechanisms of humoral memory response in the body, focusing on memory Th cells. Based on the knowledge of the protective antigen-specific memory Th cells in vivo, we now compare the localization and dynamics of protective and auto-reactive memory Th cells and then will determine how auto-reactive memory Th cells are generated, maintained and reactivated in the body, finding out the cellular and molecular targets to treat autoimmune diseases.
Sarkander J, Hojyo S, Tokoyoda K. Vaccination to gain humoral immune memory. Clin. Transl. Immunology. 5:e120, 2016
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. Myosin light chain 9 and 12 are functional ligands for CD69 that regulate airway inflammation. Science Immunol. 1:eaaf9154, 2016
Hojyo S, Sarkander J, Männe C, Mursell M, Hanazawa A, Zimmel D, Zhu J, Paul WE, Fillatreau S, Löhning M, Radbruch A, Tokoyoda K. B cells negatively regulate the establishment of CD49b+T-bet+ resting memory T helper cells in the bone marrow. Front. Immunol. 7:26, 2016
Dong J, Chang HD, Tokoyoda K, Radbruch A. Immunological memory of the bone marrow. Z. Rheumatol. 74:527-8, 2015
Sercan Alp Ö, Durlanik S, Schulz D, McGrath M, Grün JR, Bardua M, Ikuta K, Sgouroudis E, Riedel R, Zehentmeier S, Hauser AE, Tsuneto M, Melchers F, Tokoyoda K, Chang HD, Thiel A, Radbruch A. Memory CD8(+) T cells colocalize with IL-7(+) stromal cells in bone marrow and rest in terms of proliferation and transcription. Eur. J. Immunol. 45:975-987, 2015
Koji Tokoyoda, PhD
Shintaro Hojyo, PhD
Prof. Dr. Stefan H.E. Kaufmann, Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
Prof. Dr. Toshinori Nakayama, Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
Prof. Dr. Tomoko Yamamoto, Dr. Akiko Takaya, Microbiology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan