Immunology
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Koichi Kobayashi

Assistant Professor of Pathology

Department of Cancer Immunology and AIDS
Dana-Farber Cancer Institute
44 Binney Street, Dana 1420
Boston, MA 02115
Phone: 617-582-8020
Fax: 617-582-7962
email: Koichi_Kobayashi@dfci.harvard.edu
Website: The Kobayashi Lab Page
4 Postdoctoral Fellows, 1 Undergraduate Student

 

 Koichi Kobayashi

The immune system consists of two evolutionarily different but closely related arms, innate and adaptive immune responses. The harmonized interaction of these two immune responses is required for efficient combat against hazardous pathogens and cancers. Our laboratory focuses on the mechanism of the innate immune system, its connection to the adaptive immune response and disease pathogenesis caused by dysregulation of innate immune responses.

Toll-like receptor signaling. A variety of microbial products are detected by a family of germline-encoded cell surface receptors called Toll-like receptors (TLRs). TLRs are evolutionarily conserved proteins that recognize specific pathogens or Pathogen Associated Molecular Patterns (PAMPs) and trigger signaling cascades leading to host immune responses and inflammation. One of our goals is to reveal the molecular mechanisms of signaling and regulation of the Toll-like receptor system. To achieve this goal, we are using mutant mice which either lack or overexpress genes involved in TLR signaling.

NBD-LRR proteins. A recently discovered gene family casts a new light on innate immune recognition.  This cytoplasmic protein family, termed collectively NBD-LRR or Nod, is characterized by two motifs: a nucleotide binding domain (NBD) and leucine rich repeats (LRR). Genomic sequence analysis revealed that NBD-LRRs belong to a very diverse protein family. As this family shows similarity to the NBD-LRR type of disease-resistance genes in plants, it is likely that humans have NBD-LRR proteins with the purpose of detecting a broad range of pathogens. Our efforts in this area focus on the function of this protein family, especially on the mechanisms of pathogen detection and signaling cascades as well as their significance in fighting infectious diseases.

Activation of adaptive immunity by innate immunity. Activation of innate immunity, either via TLRs or NBD-LRR proteins, is a first line of defense against pathogens or cancerous cells and leads to the activation/regulation of lymphocytes, which are components of the adaptive immune system. We aim to find the mechanism of how these two systems interact with each other by using cells/animals which lack signaling molecules in the TLR and/or NBD-LRR pathways or lack NBD-LRRs per se.

Pathogenesis of inflammatory disease. Several lines of evidences suggest that poorly regulated activation of the innate immune system can contribute to chronic inflammatory diseases. Mutations of the Nod2 gene, one of the NBD-LRR members, are frequently observed in Crohn’s disease patients and TLR signaling is essential for lupus pathogenesis in certain strains of mice. We are aiming to reveal such disease pathogenesis using mouse models in which dysregulated innate immune responses cause inflammatory diseases.

 

Papers & Publications

  1. Shinohara, M. L., Lu, L., Bu. J., Werneck, M. B. F, Kobayashi, K. S., Glimcher, L. H., Cantor, H. (2006) Osteopontin expression is essential for production of IFN-a by plasmacytoid dendritic cells, Nat Immunol
  2. Zamboni, D. S., Kobayashi, K. S., Kohlsdorf, T., Ogura, Y., Long, E. M., Vance, R. E., Kuida, K., Mariathasan, S., Dixit, V. M., Flavell, R. A., Dietrich, W. F., Roy, C. R. (2006). The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection, Nat. Immunol Epub ahead of print.
  3. Kobayashi, K. S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nuñez, G., Flavell, R. A. (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract, Science307, 731-4.
  4. Kobayashi, K. S., Elizabeth E. Eynon., and Flavell, R. A. (2003). Intracellular debugging, Nat. Immunol 4, 652-654.
  5. Kobayashi, K., Hernandez, L. D., Galan, J. E., Janeway, C. A., Jr., Medzhitov, R., and Flavell, R. A. (2002). IRAK-M is a negative regulator of Toll-like receptor signaling, Cell 110, 191-202.
  6. Kobayashi, K., Inohara, N., Hernandez, L. D., Galan, J. E., Nunez, G., Janeway, C. A., Medzhitov, R., and Flavell, R. A. (2002). RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems, Nature 416, 194-9.