Clear insights into signaling between molecules involved in the immune response have recently been revealed by Japanese immunologists. The immune response is triggered when invading pathogens are recognized by receptors found on the surface of white blood cells, namely lymphocytes and myeloid cells.
Lymphocytes play an integral role in acquired immunity, which enables the body to recognize and remember invading pathogens precisely and develop stronger attacks against them after each encounter. Acquired immunity is triggered when a pathogen evades the innate immune system, which recognizes, and responds to, pathogens as a pattern in a generic way. Myeloid cells are implicated in this innate immunity.
The major types of lymphocytes are B cells and T cells that have B cell- (BCR) and T cell- (TCR) receptors respectively. Myeloid cells, such as dendritic cells and macrophages, have microbe-responsive surface receptors including toll-like receptors (TLRs), Fc receptors and lectin receptors. When any of these receptors recognize a pathogen, they trigger gene expression and subsequent immune protective responses through their association with unique signaling molecules. The activation signal is transmitted through pathways involving adaptor proteins that mediate the process.
Two such adaptors are the well-characterized CARMA1 and a closely related protein, CARD9. CARMA1 is expressed in lymphocytes and is an essential signaling mediator in the pathway that links TCR and BCR to gene activation for acquired immunity. CARD9 seems to be the CARMA1 counterpart in myeloid cells.
In a recent paper published in Nature Immunology (1), Takashi Saito of the RIKEN Research Center for Allergy and Immunology and his colleagues describe their work on mice lacking the CARD9 and CARMA1 adaptors (Fig. 1).
Many receptors responsible for antigen-recognition in both lymphocytes and myeloid cells mediate signals through adaptors that contain a module called an ITAM (immunoreceptor tyrosine-based activation motif). The team provides genetic evidence that all myeloid receptors that initiate signals through an ITAM-containing adaptor need CARD9 and another adaptor protein, Bcl-10, to activate innate immune responses. They also demonstrate that TLR-dependent signaling pathways in myeloid cells converge on CARD9. The team’s results demonstrate the essential function of the CARD9-Bcl-10 complex in myeloid cells, and the innate immune response, while CARMA1-Bcl-10 complex in the lymphoid cells of the adaptive immune system.
“Therapeutic approaches targeting either the lymphoid CARMA1 complex or the myeloid CARD9 complex might provide a strategy for specifically modulating lymphoid versus myeloid cells for the activation or inhibition of their functional responses,” Saito says. Such control would ultimately benefit the treatment of autoimmune disorders and infectious diseases.
Hara, H., Ishihara C., Takeuchi, A., Imanishi, T., Xue, L., Morris, S.W., Inui, M., Takai, T., Shibuya, A., Saijo, S., Iwakura, Y., Ohno, N., Koseki, H., Yoshida, H., Penninger, J., Saito, T. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nature Immunology 8, 619–629 (2007).
