Harvard Medical School


Contact Information:

Deptartment of Microbiology and Immunobiology

Department of Cancer Immunology & AIDS

Dana Farber Cancer Institute

450 Brookline Avenue

Dana 1420

Boston, MA 02215

phone: 617-582-8020

fax: 617-582-7962


Koichi_Kobayashi@dfci.harvard.edu

Division of Immunology

Research Summary

The immune system consists of two evolutionarily different but closely related arms, innate and adaptive immune responses. Harmony between these two immune responses is required for efficient combat against hazardous pathogens and cancers. Our laboratory focuses on the mechanisms of the innate immune system, its connection to the adaptive immune response, and disease pathogenesis resulting from 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 determine the molecular mechanisms involved in Toll-like receptor signaling and regulation. To achieve this goal, we are using mutant mice that lack genes involved in TLR signaling.

NLR (NBD-LRR) proteins. The NLR cytoplasmic protein family is characterized by two motifs: a nucleotide binding domain (NBD) and leucine rich repeats (LRRs). NLRs belong to a very diverse protein family. Our efforts are focused on elucidating the function of this protein family, especially on their mechanisms of pathogen detection and downstream signaling cascades, as well as their significance in fighting infectious diseases.

Activation of adaptive immunity by innate immune responses. Activation of innate immunity, either via TLRs or NLR proteins, is a first line of defense against pathogens and leads to the activation/regulation of lymphocytes, which are components of the adaptive immune system. It had been shown previously that an NLR protein, CIITA, is a transactivator of MHC class II genes, and we have recently found that the NLR protein NLRC5/Nod27 is a transactivator of MHC class I genes. We aim to find the mechanisms by which the innate and adaptive immune systems interact and synergize.

Pathogenesis of inflammatory disease. Several lines of evidences suggest that poor regulation of innate immune responses can contribute to chronic inflammatory diseases. Mutations of the NLR family member NOD2 are frequently observed in Crohn’s disease patients, and TLR signaling is essential for lupus pathogenesis in certain strains of mice. We study the role of TLR and NLR function in disease pathogenesis using mouse models in which dysregulated innate immune responses cause inflammatory diseases.

Selected Publications

Meissner, T.B., Li A., Biswas, A., Lee, K-H., Liu, Y-J., Bayir, E., Iliopoulos, D., van den Elsen, P., Kobayashi, K.S. (2010) NLR family member NLRC5 is a transcriptional regulator of MHC class I genes.
Proc Natl Acad Sci U S A, 107(31): 13794-9.

Biswas, A., Liu, Y-J., Hao, L., Mizoguchi, A., Salzman, N.H., Bevins, C.L., Kobayashi, K.S. (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum.
Proc Natl Acad Sci U S A, 107(33):14739-44.

Petnicki-Ocwieja, T., Hrncir, T., Yuen-Joyce Liu, Y-J., Biswas, A., Hudcovic, T., Tlaskalova-Hogenovac, H., Kobayashi, K.S. (2009). Nod2 is required for the regulation of commensal microbiota in the intestine.
Proc Natl Acad Sci U S A, 106(37):15813-8.

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 7(3):318-25.

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,
Science 307, 731-4.

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.