Research

Molecular mechanisms involved in regulation of immune responses

The Project Leader's Profile

Hitoshi Kikutani

Professor, Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University

Project Leader
  • Hitoshi Kikutani, Professor
Research Members
  • Teruhito Yasui, Associate professor
  • Masayuki Mizui, Assistant professor

Summary

T cells are activated by antigenic peptides bound to MHC complex on antigen-presenting cells. Once activated, the T cells differentiate into functional, helper or effector T cells. On the other hand, antigen-stimulated B cells differentiate into antibody-forming cells or memory B cells with the help of antigen-specific T cells. Thus, T- and B-cell differentiation requires physiological interactions between T cells and antigen-presenting cells and also between T cells and B cells, respectively. Such cell-cell interactions are mediated by a variety of costimulatory molecules, including CD40, CD40 ligand, B-7 and CD28. In addition, it has recently been revealed that several members of the semaphorin family are crucially involved in immune cell interactions. We are currently studying the roles of these molecules in regulation of immune responses.

1) Mechanisms of immune regulation by semaphorin molecules

The semaphorin family has been identified as axonal guidance factors that function during neuronal development. However, a series of studies by our laboratory have shown that several semaphorin molecules play crucial roles at various stages of immune responses. For instance, Sema4D/CD100 is involved in the activation of B cells and dendritic cells, while Sema4A plays roles not only in T cell priming but also in Th1 differentiation. The interaction between Sema6D and its receptor Plexin-A1 is also shown to play roles in cellular immune responses by activating dendritic cells and bone homeostasis by inducing osteoclastgenesis. Furthermore, we have recently demonstrated that Sema7A on activated T cells activates macrophages to produce inflammatory cytokines and triggers inflammatory responses through α1β1 integrin (Figure 1).

fig1.gifFigure 1. semaphorins and their multiple receptors
Various types of semaphorins, including secreted, transmembrane, truncated and GPI-anchored forms, function during immune responses. However, some semaphorins utilize receptors in the immune system that are distinct from receptors in the nervous system.



2) Molecular pathogenesis by which Epstein-Barr virus (EBV) induces immunological disorders
EBV is a human herpesvirus that causes infectious mononucleosis in healthy donors and proliferative disorders in immune-suppressive conditions induced by aging, immunesuppresant therapy and HIV infection. In some case it has been considered that EBV infection is associated with B cell malignancies such as Burkitt's lymphomas and Hodgkin's lymphomas and also with some autoimmune diseases of which Systemic lupus erythematosus (SLE) and Multiple sclerosis (MS) are developed. It infects B cells latently and is prevalent worldwide. By studying EBV biology, we are keen to determine how EBV leads to human carcinogenesis. Furthermore, the outcomes from this study may reveal attractive therapeutic strategies for EBV-associated immune disorders (Figure 2).

fig2Figure 2. EBV and host immune system
The mechanism by which EBV induces human B cell growth transformation is closely associated with the vulnerability of host immune system.

Some of Recent Papers

  1. Yasui, T., et al. (2004). Latent infection membrane protein transmembrane FWLY is critical for intramolecular interaction, raft localization, and signaling. Proc. Natl. Acad. Sci, USA. 101, 278-83.
  2. 2. Kumanogoh, A., et al. (2005) Non-redundant roles of Sema4A in the immune system: Defective T-cell priming and Th1/Th2 regulation in sema4A-deficient mice. Immunity 22, 305-316.
  3. Takegahara, N., et al. (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nature Cell Biol., 8,615-622.
  4. Suzuki, K., et al. (2007). Semaphorin 7A initiates T cell-mediated inflammatory resonses through α1β1 integrin. Nature, 446,680-684.
  5. Suzuki, K., Kumanogoh, A., Kikutani, H. (2008) Semaphorins and their receptors in immune cell interactions. Nat. Immunol., 9, 17-23.