Osteoimmunology

Roles of memory T helper lymphocytes in protective immunological memory

Tokoyoda

Introduction

Memory T helper (Th) lymphocytes are critical for the generation, maintenance and reactivation of other memory cells and play a crucial role in maintaining and provoking protective memory to infectious pathogens and pathogenic memory to autoantigens. Despite their central role, the generation, maintenance and reactivation of pathogen-specific and auto-reactive memory Th cells in the body still remain unclear.

Recently, we have found and further described the microenvironment ‘niches’ for survival of pathogen-specific memory plasma cells and memory Th cells in the bone marrow (BM). Memory plasma cells adhere to CXCL12-expressing stromal cells and memory Th cells are maintained on IL-7-expressing stromal cells. Although it had been commonly thought that memory Th cells are circulating and maintained antigen-dependently, we exhibited that pathogen-specific memory Th cells are not circulating and instead reside and rest in the BM antigen-independently. In 2012 and 2013, we have reported that CD69 and CD49b (integrin alpha2) are required as homing receptors for the generation and maintenance of pathogen-specific memory Th cells in the BM.

We have so far shown how pathogen-specific memory Th cells are generated and maintained in the body. There is still much to discover about the reactivation of pathogen-specific memory Th cells, i.e. memory response, and also about the generation and maintenance of auto-reactive memory Th cells. In the case of memory response, the complex and still widely unknown collaboration by BM memory Th cells and splenic memory B cells should be clarified. We currently study the cellular and molecular mechanisms of humoral memory response in the body, focusing on memory Th cells. For auto-reactive memory Th cells, comparing them with pathogen-specific memory cells, we aim at understanding how auto-reactive memory Th cells are generated and maintained in the body.

Selected Publications

1. 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.

2. 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.

3. Okhrimenko A, Grün JR, Westendorf K, Fang Z, Reinke S, von Roth P, Wassilew G, Kühl AA, Kudernatsch R, Demski S, Scheibenbogen C, Tokoyoda K, McGrath MA, Raftery MJ, Schönrich G, Serra A, Chang HD, Radbruch A, Dong J. Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory. Proc. Natl. Acad. Sci. USA. 111:9229-9234, 2014.

4. Yokota M, Suzuki K, Tokoyoda K, Meguro K, Hosokawa J, Tanaka S, Ikeda K, Mikata T, Nakayama T, Kohsaka H, Nakajima H. Roles of mast cells in the pathogenesis of inflammatory myopathy. Arthritis Res. Ther. 16:R72, 2014.

5. Tsuneto M, Kajikhina E, Seiler K, Reimer A, Tornack J, Bouquet C, Simmons S, Knoll M, Wolf I, Tokoyoda K, Hauser A, Hara T, Tani-ichi S, Ikuta K, Grün JR, Grützkau A, Engels N, Wienands J, Yanagisawa Y, Ohnishi K, Melchers F. Environments of B cell development. Immunol. Lett. 157:60-63, 2014.

Members

Group leader:
Koji Tokoyoda, PhD

Scientists:
Shintaro Hojyo, PhD

PhD students:
Jana Sarkander
Christian Männe
Mathias Mursell

Students:
Yasemin Keziban
Ali Awada

Student assistant
Tsung-Yen Wu

Cooperation partners

Prof. Dr. Max Löhning, DRFZ, Experimental Immunology, Berlin, Germany

Prof. Dr. Toshinori Nakayama, Immunology, Chiba University, Chiba, Japan

Prof. Dr. Andreas Radbruch, DRFZ, Cell Biology, Berlin, Germany

Prof. Dr. Tomoko Yamamoto, Dr. Akiko Takaya, Microbiology, Chiba University, Chiba, Japan

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
Bone marrow
Secondary immune response
Humoral immunity