Researches in the Koyasu Laboratory

We focus our efforts on Immunology. In particular, we are interested in infectious immunity and autoimmunity. By employing genetics as well as molecular and cellular biology, we try to understand the principle of regulatory mechanisms of immune responses. Although we work hard, we enjoy science at the same time. We do not follow other people's research. Our goal is to discover something new and unique in the field of immunology. Please read our papers to know more about our work. Following are topics on which we are currently working.

1) Studies on infectious immunity. We employ various infectious agents to understand the strategy of both microbes and the host. In particular, we believe that dendritic cells are important in both innate and adaptive immunity and study the function of dendritic cells in various phases of infection. Microbes include Listeria monocytogenes, Helicobacter pylori, Enteropathogenic Escherichia coli, Leishmania major and Storngylloides venezuelensiss.

Chiba, S., Nagai, T., Hayashi, T., Baba, Y., Nagai, S., and Koyasu S. (2011) Listerial invasion protein internalin B promotes the entry into ileal Peyer’s patches in vivo. Microbiol. Immunol. 55:123-129.

Hayashi, T., Nagai, S., Fujii, H., Baba, Y., Ikeda, E., Kawase, T., and Koyasu, S. (2009) Critical roles of NK and CD8⁺ T cells in CNS listeriosis. J. Immunol. 182(10):6360-6368.

Nagai, S., Mimuro, H., Yamada, T., Baba, Y., Moro, K., Nochi, T., Kiyono, H., Suzuki, T., Sasakawa, C., and Koyasu, S. (2007) Role of Peyer's patches in the induction of Helicobacter pylori-induced gastritis. Proc. Natl. Acad. Sci. USA. 104:8971-8976.

Ohteki, T., Tada, H., Ishida, K., Sato, T., Maki, C., Yamada, T., Hamuro, J., and Koyasu, S. (2006) Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J. Exp. Med. 203: 2329-2338.

Suzue, K., Asai, T., Takeuchi, T., and Koyasu, S. (2003) In vivo role of IFN-g produced by antigen presenting cells in early host defense against intracellular pathogens. Eur. J. Immunol. 33:2666-2675.

Ohteki, T., Suzue, K., Maki, C., Ota, T., and Koyasu, S. (2001) Critical role of IL-15-IL-15R for antigen-presenting cell functions in the innate immune response. Nat. Immunol. 2:1138-1143.

Fukao, T., Frucht, D. M., Yap, G., Gadina, M., O’Shea, J. J. and Koyasu, S. (2001) Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J. Immunol. 166:4446-4455.

Fukao, T., and Koyasu, S. (2000) Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30:1453-1457.

Fukao, T., Matsuda, S., and Koyasu, S. (2000) Synergistic effects of IL-4 and IL-18 on IL-12 dependent interferon-g production by dendritic cells. J. Immunol. 164:64-71.

Ohteki, T., Fukao, T., Suzue, K., Maki, C., Ito, M., Nakamura, M., and Koyasu, S. (1999) Interleukin-12 dependent interferon-g production by CD8a⁺ lymphoid dendritic cells. J. Exp. Med. 189:1981-1986.

2) Studies on a new lymphocyte “Natural Helper Cell”. We have identified a new lymphoid tissue in mouse and human mesentery and termed ed this tissue fat-associated lymphoid cluster (FALC). We also discovered a new innate lymphocyte subset producing of Th2 cytokines and named this new lymphocyte “Natural Helper (NH) Cell”. NH cells support the proliferation of B1 cells in the peritoneal cavity and induce goblet cell hyperplasia during the innate phase of nematode infection.

Koyasu, S. and Moro, K. (2011) Type 2 innate immune responses and the natural helper cell. Immunology 132:475-481.

Koyasu, S. and Moro, K. (2011) Innate Th2-type immune responses and the Natural Helper Cell, a newly identified lymphocyte population. Curr. Opin. Allergy Clin. Immunol. 11:109-114.

Koyasu, S., Moro, K., Tanabe, M., and Takeuchi, T. (2010) Natural Helper Cells: a new player in the innate immune response against helminth infection. Adv. Immunol. 108:21-44.

Moro, K., Yamada, T., Tanabe, M., Takeuchi, T., Ikawa, T., Kawamoto, H., Furusawa, J.-I., Ohtani, M., Fujii, H., and Koyasu, S. (2010) Innate production of Th2 cytokines by adipose tissue-associated c-Kit⁺Sca-1⁺ lymphoid cells. Nature 463: 540-544.

3) Role of phosphoinositide 3-kinase (PI3K) in immune cells. Using mice deficient for p85a, a regulatory subunit of class IA PI3K, we study the role of PI3K in various phases of immune responses as well as development of immune cells.

Kurebayashi Y, Nagai S, Ikejiri A, Koyasu S. (2013) Recent Advances in Understanding the Molecular Mechanisms of the Development and Function of Th17 Cells. Genes Cells in press. (2013, Feb 5, doi: 10.1111/gtc.12039).

Kurebayashi, Y., Nagai, S., Ikejiri, A., Ohtani, M., Ichiyama, K., Baba, Y., Yamada, T., Egami, S., Hoshii, T., Hirao, A., Matsuda, S., Koyasu, S. (2012) PI3K-Akt-mTORC1-S6K1/2 Axis Controls Th17 Differentiation by Regulating Gfi1 Expression and Nuclear Translocation of RORg. Cell. Rep. 1:360-373.

Matsuda, S., Mikami, Y., Ohtani, M., Fujiwara, M., Hirata, Y., Minowa, A., Terauchi, Y., Kadowaki, T., and Koyasu, S. (2009) Critical role of class IA PI3K for c-Rel expression in B lymphocytes. Blood 113:1037-1044.

Ohtani, M., Nagai, S., Kondo, S., Mizuno, S., Nakamura, K., Tanabe, M., Takeuchi, T., Matsuda, S., and Koyasu, S. (2008) Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate LPS-induced IL-12 production in dendritic cells. Blood 112:635-643.

Shiroki, F., Matsuda, S., Doi, T., Fujiwara, M., Mochizuki, Y., Kadowaki, T., Suzuki, H., and Koyasu, S. (2007) The p85a regulatory subunit of class IA phosphoinositide 3-kinase regulates b -selection in thymocyte development. J. Immunol. 178:1349-1356.

Suzuki, H., Matsuda, S., Terauchi, Y., Fujiwara, M., Ohteki, T., Asano, T., Behrens, T. W., Kouro, T., Takatsu, K., Kadowaki, T., and Koyasu, S. (2003) PI3K and Btk differentially regulate B cell antigen receptor mediated signal transduction. Nat. Immunol. 4:280-286.

Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T., and Koyasu, S. (2002) PI3K-mediated negative feedback regulation of IL-12 production in dendritic cells. Nat. Immunol. 3:875-881.

Fukao, T., Yamada, T., Tanabe, M., Terauchi, Y., Ota, T., Takayama, T., Asano, T., Takeuchi, T., Kadowaki, T., Hata, J., and Koyasu, S. (2002) Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. Nat. Immunol. 3:295-304.

Suzuki, H., Terauchi, Y. Fujiwara, M., Aizawa, S., Yazaki, Y., Kadowaki T., and Koyasu, S. (1999) Xid-like immunodeficiency in mice with disruption of the p85a subunit of phosphoinositide 3-kinase. Science 283:390-392.

4) Studies on autoimmune disease model mice. We have established a novel method to generate autoimmune model mice in collaboration with Department of Dermatology. In a given knockout mouse self tolerance against the defective molecule is not acquired. Adoptive transfer of lymphocytes from such autoantigen knockout mice after immunization with antigens into antigen-positive mice should provide an active disease animal model for autoimmune diseases. We have applied this method to a well-characterized autoimmune disease, pemphigus valgaris, a well-defined life-threatening autoimmune disease against skin and mucous membranes. We are also trying to establish autoimmune mice against different antigens. These mice will be valuable in evaluating various reagents to treat the diseases. We also employ collagen-induced arthritis model mice to study the role of dendritic cells on the onset of arthritis.

Yoshizawa, A., Nagai, S., Baba, Y., Yamada, T., Matsui, M., Tanaka, H., Miyoshi, S., Amagai, M., Yoshikawa, T., Fukuda, K., Ogawa, S., Koyasu, S. (2012) Autoimmunity against M2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy-like phenotype. Eur. J. Immunol. 42:1152-63.

Matsui, T., Nakata, N., Nagai, S., Nakatani, A., Takahashi, M., Momose, T., Ohtomo, K., and Koyasu, S. (2009) Inflammatory cytokine and hypoxia contribute to ¹⁸F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis. J. Nucl. Med. 50:920-926.

Ota, T., Aoki-Ota, M., Tsunoda, K., Nishikawa, T., Koyasu, S., and Amagai, M. (2008) Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen: implications for peripheral tolerance. Int. Immunol. 20:1351-1360.

Ota, T., Aoki-Ota, M., Tsunoda, K., Simoda, K., Nishikawa, T., Amagai, M., and Koyasu, S. (2004) Auto-reactive B cells against peripheral antigen, desmoglein 3, escape from tolerance mechanism. Int Immunol. 16:1487-1495.

Tsunoda, K., Ota, T., Suzuki, H., Ohyama, M., Nagai, T., Nishikawa, T., Amagai, M., and Koyasu, S. (2002) Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris. Eur. J. Immunol. 32:627-633.

Amagai, M., Tsunoda, K., Suzuki, H., Nishifuji, K., Koyasu, S., and Nishikawa, T. (2000) Use of autoantigen knockout mice to develop an active autoimmune disease model. J. Clin. Invest. 105:625-631.

5) Studies on HIV. Dr. Shingo Kato’s group studies on the mechanisms of drug resistance of HIV.

Kuji, N., Yoshii, T., Hamatani, T., Hanabusa, H.,, Yoshimura Y., and Kato, S. (2008) Buoyant density and sedimentation dynamics of HIV-1 in two density-gradient media for semen processing. Fertil. Steril. 90:1983-1987.

Tanaka, R., Hanabusa, H., Kinai, E., Hasegawa, N., Negishi, M., and Kato, S. (2008) Intracellular efavirenz levels in peripheral blood mononuclear cells from human immunodeficiency virus-infected individuals. Antimicrob. Agents Chemother. 52:782-785.

Kinai, E., Hanabusa, H., and Kato, S. (2007) Prediction of the efficacy of antiviral therapy for hepatitis C virus infection by an ultrasensitive RT-PCR assay. J. Med. Virol. 79:1113-1119.

Kato, S., Hanabusa, H., Kaneko, S., Takakuwa, K., Suzuki, M., Kuji, N., Jinno, M., Tanaka, R., Kojima, K., Iwashita, M., Yoshimura, Y., and Tanaka, K. (2006) Complete removal of HIV-1 RNA and proviral DNA from semen by the swim-up method: assisted reproduction technique using spermatozoa free from HIV-1. AIDS 20:967-973.

Kato, S., Saito, Y., Tanaka, R., Hiraishi, Y., Kitamura, N., Matsumoto, T., Hanafusa, H., Kamakura, M., Ikeda, Y., and Negishi, M. (2003) Differential prevalence of HIV-1 subtype B and CRF01_AE among different sexual transmission groups in Tokyo, Japan, as revealed by subtype-specific PCR. AIDS Res. Hum. Retrovirus 19:1057-1063.

Kato, S., Hiraishi, Y., Nishimura, N., Sugita, T., Tomihama, M., and Takano, T. (1998) A plaque hybridization assay for quantifying and cloning infectious human immunodeficiency virus type 1 virions. J. Viol. Methods 72:1-7.