Dr. Koichi Kobayashi, M.D., Ph.D.

College of Medicine
Texas A&M Health Science Center.

Title: NLRC5/CITA: a critical regulator of MHC class I antigen-presentation and cancer immunity
June 22nd: 12 pm EST, 11 am CST, 9 am PST

Education and Training

    Ph.D, Immunology, Chiba University School of Medicine, Chiba, Japan (1998)
    M.D., Chiba University School of Medicine, Chiba, Japan (1991)

Research Interests

 The recognition of microbes is mediated by pattern recognition receptors (PRRs). Toll-like receptors (TLRs), RIG-like receptors (RLRs), C-type lectin-like receptors (CLRs) and nucleotide-binding oligomerization domain-leucine rich repeat containing (NLR) proteins serve as PRRs that recognize different but overlapping microbial components. The most diverse family of PRRs in animals are the NLRs. Mutations in one NLR gene, NOD2, are associated with susceptibility to inflammatory diseases such as Crohn's disease, and mutations in another member, NALP3, are important for susceptibility to familial cold autoinflammatory syndrome and Muckle-Wells syndrome. The mammalian NLR family
serves as a recognition system to protect hosts against pathogens, however, their mutations may enhance susceptibility to inflammatory diseases.

 The major goal of my laboratory is to understand the function of the innate immune system, particularly in host-pathogen recognition and disease pathophysiology. We elucidated physiological function of Nod2 in the intestine. We showed that Nod2 is important for the function of ileal crypts, which exert bacteria killing activity through the secretion of antibacterial compounds. We found that Nod2 is not only important for controlling intestinal bacterial infection but also for the regulation of commensal bacterial flora at steady-state. We furthermore established an animal model for Nod2-dependent, Th1-dominant granulomatous ileitis, which is useful for Crohn’s disease research because of its similarity to the human disease. More recently, we have found that another NLR family member, NLRC5, is a transcriptional 25 regulator of MHC class I molecules and related genes. Although CIITA has been known as a master regulator of MHC class II genes for the last two decades, a counterpart regulator of MHC class I genes had not been identified. We have shown that NLRC5 specifically regulates MHC class I genes and is not redundant to CIITA, indicating that NLRC5 is a critical component of MHC class I/ CD8-mediated immune responses.

Our current areas of investigation include: 1) The functions and molecular mechanisms of cytoplasmic NLR family proteins. 2) The role of TLR and NLR proteins in host-pathogen interaction. 3) The pathogenesis of inflammatory diseases caused by dysregulated innate immune responses using molecular and cell biology, as well as gene-targeting approaches.

Selected Publications

Yoshihama S, Roszik J, Downs I, Meissner TB, Vijayan S, Chapuy B, Sidiq T, Shipp MA, Lizee GA, Kobayashi KS.
NLRC5/MHC class I transactivator is a target for immune evasion in cancer.
Proc Natl Acad Sci U S A. 2016 May 24;113(21):5999-6004.

Downs I, Vijayan S, Sidiq T, Kobayashi KS.
CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression.
Biofactors. 2016 Apr 18.

Burrows MP, Volchkov P, Kobayashi KS, Chervonsky AV.
Proc Natl Acad Sci U S A. 2016 May 24;113(21):5999-6004.

Shiu J, Piazuelo MB, Ding H, Czinn SJ, Drakes ML, Banerjee A, Basappa N, Kobayashi KS, Fricke WF, Blanchard TG.
Gastric LTi cells promote lymphoid follicle formation but are limited by IRAK-M and do not alter microbial growth.
Mucosal Immunol. 2015 Sep;8(5):1047-59

Miyata M, Lee JY, Susuki-Miyata S, Wang WY, Xu H, Kai H, Kobayashi KS, Flavell RA, Li JD.
Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M.
Nat Commun. 2015 Jan 14;6:6062.

Lech M, Gröbmayr R, Ryu M, Lorenz G, Hartter I, Mulay SR, Susanti HE, Kobayashi KS, Flavell RA, Anders HJ.
Macrophage phenotype controls long-term AKI outcomes–kidney regeneration versus atrophy.
J Am Soc Nephrol. 2014 Feb;25(2):292-304.

Shiu J, Czinn SJ, Kobayashi KS, Sun Y, Blanchard TG.
IRAK-M expression limits dendritic cell activation and proinflammatory cytokine production in response to Helicobacter pylori.
PLoS One. 2013 Jun 11;8(6):e66914.

Klimesova K, Kverka M, Zakostelska Z, Hudcovic T, Hrncir T, Stepankova R, Rossmann P, Ridl J, Kostovcik M, Mrazek J, Kopecny J, Kobayashi KS, Tlaskalova-Hogenova H.
Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice.
Inflamm Bowel Dis. 2013 May;19(6):1266-77.

Mingueneau M, Kreslavsky T, Gray D, Heng T, Cruse R, Ericson J, Bendall S, Spitzer MH, Nolan GP, Kobayashi K, von Boehmer H, Mathis D, Benoist C; Immunological Genome Consortium, Best AJ, Knell J, Goldrath A, Joic V, Koller D, Shay T, Regev A, Cohen N, Brennan P, Brenner M, Kim F, Nageswara Rao T, Wagers A, Heng T, Ericson J, Rothamel K, Ortiz-Lopez A, Mathis D, Benoist C, Bezman NA, Sun JC, Min-Oo G, Kim CC, Lanier LL, Miller J, Brown B, Merad M, Gautier EL, Jakubzick C, Randolph GJ, Monach P, Blair DA, Dustin ML, Shinton SA, Hardy RR, Laidlaw D, Collins J, Gazit R, Rossi DJ, Malhotra N, Sylvia K, Kang J, Kreslavsky T, Fletcher A, Elpek K, Bellemare-Pelletier A, Malhotra D, Turley S.
The transcriptional landscape of αβ T cell differentiation.
Nat Immunol. 2013 Jun;14(6):619-32. doi: 10.1038/ni.2590. Epub 2013 May 5. PMID: 23644507

 Biswas A, Kobayashi KS.
Regulation of intestinal microbiota by the NLR protein family.
Int Immunol. 2013 Apr;25(4):207-14. 

Kobayashi, K.S. and van den Elsen, P. (2012) NLRC5/MHC class I transactivator: a key regulator of class I mediated immune responses. Nat Rev Immunol, 12(12):813-20.

Lee, K-H., Biswas, A., Liu, Y-J., Kobayashi, K.S. (2012) Proteasomal degradation of Nod2 mediates tolerance to bacterial cell wall components. J. Biol Chem, 287(47):39800-11.

Hoogerwerf J.J., van der Windt G.J., Blok D.C., Hoogendijk A.J., de Vos A.F., van 't Veer C., Florquin S., Kobayashi K.S., Flavell R.A., van der Poll T. (2012) Interleukin-1-receptor-associated kinase M deficient mice demonstrate an improved host defense during gram-negative pneumonia. Mol Med, 18(1):1067-75.

Sukumaran, B., Ogura Y, Pedra, J., Kobayashi, K.S., Flavell R.A., Figrig, E. (2012) Rip2 contributes to host defense against Anaplasma phagocytophilum infection. FEMS Immunol Med Micro, 2012; 66(2):211-9

Kobayashi, K.S. (2012) NLRC5/CITA: a novel regulator of class I major histocompatibility complex genes. J Immunodef Diorders, 2012; in press.

Biswas, A., Meissner, T.B., Kawai, T., Kobayashi, K.S. (2012) Impaired MHC Class I Expression in Mice Deficient for Nlrc5/CITA. J Immunol, 189(2):516-20

Koo, J-E., Hong, H-J., Dearth, A., Kobayashi, K.S.* Koh, Y-S.* (2012) Intracellular invasion of Orientia tsutsugamushi activates inflammasome in ASC-dependent manner. PLoS One, 2012; 7(6):e39042.

Balamayooran, T., Batra, T.S., Balamayooran, G., Cai, S., Kobayashi K.S., Flavell, R.A., Jeyaseelan, S. (2012) NOD2 Signaling Contributes to Host Defense in the Lungs Against E. coli Infection.  Infect Immun, 80(7):2558-69.

van der Windt G.J., Blok D.C., Hoogerwerf J.J., Lammers A.J., de Vos A.F., van 't Veer C., Florquin S., Kobayashi K.S., Flavell R.A., van der Poll T. (2012) IL-1-receptor-associated kinase M impairs host defense during pneumococcal pneumonia. J Infect Dis, 205(12):1849-57.

Meissner, T.B., Liu, Y-J., Lee, K-H., Li A., Biswas, A., van Eggermond, M.C.J.A., van den Elsen, P., Kobayashi, K.S. (2012) NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J Immunol, 188(10):4951-8.

Meissner, T.B., Li A., Liu, Y-J., Gagnon, E., Kobayashi, K.S.,  (2012) The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity. Biochem Biophys Res Commun, 418(4):786-91.

Delhase M, Kim S.Y., Lee H., Naiki-Ito A., Chen Y., Ahn E.R., Murata K, Kim S.J., Lautsch N., Kobayashi K.S., Shirai T., Karin M., Nakanishi M. (2012) TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2. Proc Natl Acad Sci USA, 109(4):E177-86.

Meissner, T.B., Li A., Kobayashi, K.S. (2012) NLRC5: a newly discovered MHC class I transactivator (CITA) Microbes Infect, 14(6):477-84.

Zhao, Y., Cotoner, C.A., Chung, E., Ballester, I., Chang, S-Y., Guleng, B., Arihiro, S., Murray, P. J., Guleng, B., Xavier, R., Kobayashi, K.S., Reinecker, H., C. (2012) Control of NOD2 and Rip2 dependent innate immune activation by GEF-H1. Inflamm Bowel Dis, 18(4):603-12.

Biswas, A.,Petnicki-Ocwieja, T., Kobayashi, K.S. (2012) Nod2: a key regulator linking microbiota to intestinal mucosal immunity J. Mol Med, 90(1):15-24.

Ogawa, C., Liu, Y-J., Kobayashi, K.S. (2011) Muramyl dipeptide and its derivatives: Peptide adjuvant in immunological disorders and cancer therapy. Curr. Bio. Comp, 2011; 7(3):180-197.

Petnicki-Ocwieja, T., DeFrancesco, A., Chung, E., Darcy, C, T., Bronson, R., T., Kobayashi, K.S. Hu, L., T. (2011) Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis through the induction of tolerance. PLoS One, 2011; 6(2):e17414.

Lee, K-H., Liu, Y-J., Biswas, A., Ogawa, C., Kobayashi, K.S. (2011) A novel aminosaccharide compound blocks immune responses by Toll-like receptors and Nucleotide-binding domain, leucine-rich repeat   proteins. J. Biol. Chem, 286(7):5727-35.

Biswas, A., Wilmanski, J., Forsman, H., Hrncir, T., Hao, L., Tlaskalova-Hogenova, H., Kobayashi, K.S. (2011) Negative regulation of Toll-like receptor signaling plays an essential role in the homeostasis of the intestine. Eur. J. Immunol., 41(1):182-94.

Biswas A, Liu YJ, Hao L, Mizoguchi A. Salzman NH, Bevins CL, Kobayashi KS. (2010). Induction and rescue of Nod2-dependent Th1-driven granulomatous inflamemation of the ileum. Proc Natl Acad Sci USA. 107(33):14739-44.

Koh YS, Koo JE, Biswas A, Kobayashi KS. (2010). MyD88-dependent signaling contributes to host defense against ehrlichial infection. PLoS One. Jul 23:5(7):el1758

Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E. Iliopoulos D, van den Elsen PJ, Kobayashi KS. (2010). NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci USA. 107 (31): 13794-9.

Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H, Kobayashi KS. (2009). Nod2 is required for the regulation of commensal microbiota in the intestine. Proc natl Acad Sci USA. Sep 15;106(37):15813-8. Epub 2009 Sep 1.

Matza, D., Kobayashi, K. S., Badou, A., Goldsmith-Pestana, K., Masuda, Y., Komuro, A., McMahon-Pratt, D., Marchesi, V. T. and Flavell, R. A. (2008) A scaffold protein, AHNAK1 is required for calcium signaling during T cell activation,  Immunity, 28(1):64-74.

Wilmanski J. M., Petnicki-Ocwieja T., Kobayashi, K. S. (2008) NLR proteins: integral members of innate immunity and mediators of inflammatory diseases. J. Leukoc Biol, 83(1):13-30.

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 7(5):498-506.

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. S., Elizabeth E. Eynon., and Flavell, R. A. (2003). Intracellular debugging, Nat. Immunol 4, 652-654.

Kobayashi, K. S, 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.

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 signaling for receptors of the innate and adaptive immune systems, Nature 416, 194-9.