Molecular mechanisms involved in the regulation of immune responses.
T cells are activated by MHC-bound antigenic peptides on antigen-presenting cells. Once activated, the T cells differentiate into functional, helper, or effector T cells. In contrast, antigen-stimulated B cells differentiate into antibody-forming 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 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 was revealed recently that several members of the semaphorin family play crucial roles in immune cell interactions. We are currently studying how these molecules function in the regulation of immune responses.
A) Mechanisms by which semaphorin molecules regulate immune responses:
The semaphorin family molecules were first identified as axonal guidance factors that function during neuronal development. However, a series of studies by our laboratory has shown that several semaphorin molecules play crucial roles at various stages of immune responses (Figure 1). For instance, Sema4D/CD100 is involved in the activation of B cells and dendritic cells, while Sema4A participates in both T-cell priming and Th1 differentiation. The interaction between Sema6D and its receptor Plexin-A1 was also shown to participate in cellular immune responses since it activates dendritic cells and promotes bone homeostasis by inducing osteoclastgenesis. Furthermore, we demonstrated recently that Sema7A on activated T cells stimulates macrophages, which then produce inflammatory cytokines; it also triggers inflammatory responses through α1β1 integrin (Figure 2).
Fig.1. Representative immune semaphorins |
Fig. 2. Accumulation of Sema7A and ¦Á1 integrin in the immunological synapse between T cells and macrophages. |
B) Elucidation of the molecular mechanism by which B cells survive and differentiate into effector cells:
Effective responses to the invasion of non-self antigen-bearing entities require that B cells differentiate into antibody-secreting cells and memory B cells. B cell survival and differentiation are driven by B cell-antigen receptor (BCR) signaling along with the signals of members of the TNF receptor family, such as CD40 and BAFF-R, on the B cell surface. To date, our group has demonstrated the immunological significance of the molecules that are involved in the signaling pathways downstream of CD40. In particular, we found that TRAF3, which interacts with the cytoplasmic region of both CD40 and BAFF-R, plays a crucial role in B cell survival and differentiation. Furthermore, we identified a PKC family member, PKN1, which is associated with the TRAF family and serves as a negative regulator of Akt in BCR signaling. Our observations together suggest that PKN1 may be responsible for the immunological tolerance that eliminates autoreactive B cells.
Molecular mechanism by which Epstein-Barr virus (EBV) induces immunological disorders.
EBV is a human herpes virus that causes infectious mononucleosis in healthy donors and proliferative disorders in patients who are immunosuppressed because of aging, immunosuppressant therapy, or HIV infection. It appears that EBV infection may be associated with B cell malignancies such as Burkitt's lymphomas and Hodgkin's lymphomas. It may also be linked to autoimmune diseases such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS). EBV infects B cells in a latent fashion and is prevalent worldwide. We are currently studying EBV biology to determine how EBV leads to human carcinogenesis. The outcomes of this study may also reveal attractive therapeutic strategies for EBV-associated immune disorders (Figure 3).
A) The molecular mechanism by which EBV infects the human host:
EBV infection induces B cell growth transformation and immortalization. The mechanism by which EBV invades B cells involves multiple steps, namely virus entry, latency, and lytic infection. We are currently seeking to establish a system that will allow us to trace in vitro the infection dynamics of EBV and the frequency of cell growth transformation. This valuable system involves the production of recombinant EBV particles that carry the gene for GFP, which facilitates the visualization of EBV as it infects human peripheral B cells (Figure 4).
Fig.3. EBV and the host immune system. |
Fig.4. Immortalization of human peripheral blood B lymphocytes by recombinant EBV particles that carry the GFP gene. |