Randy R. Brutkiewicz, Ph.D.
Professor of Microbiology & Immunology
Associate Dean for Research and Graduate Studies
Summary of the focus of the research of Dr. Brutkiewicz
The Brutkiewicz laboratory studies immune evasion by viruses and tumors, as well as the regulation of antigen presentation by various signal transduction pathways, in both innate and adaptive immune responses.
Description and summary of research focus of the laboratory
Our studies are mainly focused on the host's innate antiviral and antitumor immune responses. In our laboratory, we study the CD1d molecule, a cell surface glycoprotein that is structurally related to major histocompatibility complex (MHC) class I molecules. These molecules present lipid antigens to a subpopulation of T cells called NKT cells. We have recently reported that the glycolipid α-glucuronosylceramide isolated from the bacterium, Sphingomonas paucimobilis, can activate NKT cells in a CD1d-dependent manner. Our more recent studies have focused on how signal transduction pathways can regulate antigen presentation in both innate (i.e., CD1d) and adaptive (e.g., MHC class II) immune responses. We have found that CD1d-mediated antigen presentation is reciprocally-regulated by the mitogen-activated protein kinases (MAPK), p38 and ERK1/2. This MAPK dichotomy is very evident following a virus infection of antigen presenting cells. Further, we have recently reported that the protein kinase C δ pathway is very critical in the control of antigen presentation by both CD1d and MHC class II (but not MHC class I) molecules. Increasing our understanding of signal transduction pathway control of antigen presentation will be of great help in the development of more effective vaccines against viruses and very useful in the treatment of various hematopoietic tumors, in which the reciprocal regulation of antigen presentation by MAPK is also observed. Our work on NKT cell arm of the host's innate antitumor response has revealed differences between different CD1d+ B and T cell tumors. In the former case, NKT cells are essential, whereas in the latter, NKT cells actually impair the host's protective response. Ongoing studies are analyzing additional mechanisms by which some tumors can evade this arm of the host's innate antitumor defenses, including those signal transduction pathways that play an important role in such activity.
- Broxmeyer, H.E., Christopherson, K.W., Hangoc, G., Cooper, S., Mantel, C.R., Renukaradhya, G.J., Brutkiewicz, R.R. CD1d expression on and regulation of murine hematopoietic stem and progenitor cells. Blood 119:5731-5741, 2012.
- Gallo, R.M., Khan, M.A., Shi, J., Kapur, R., Wei, L., Bailey, J.C., Liu, J., Brutkiewicz, R.R. Regulation of the actin cytoskeleton by Rho kinase controls antigen presentation by CD1d. J. Immunol. 189:1689-1698, 2012.
- Zeng, M.Y., Pham, D., Bagaitkar, J., Liu, J., Otero, K., Shan, M., Wynn, T.A., Brombacher, F., Brutkiewicz, R.R., Kaplan, M.H., Dinauer, M.C. An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. Blood 121:3473-3483, 2013. PMCID: PMC363701642.
- Walline, C.C., Sehra, S., Fisher, A.J., Guindon, L.M., Kratzke, I.M., Montgomery, J.B., Lipking, K.P., Glosson, N.L., Benson, H.L., Sandusky, G.E., Wilkes, D.S., Brutkiewicz, R.R., Kaplan, M.H., Blum, J.S. Allergic airway disease in mice alters T and B cell responses during an acute respiratory poxvirus infection. PLoS ONE 8(4):e62222, 2013. PMCID: PMC3631162.
- Liu, J., Glosson, N., Du, W., Gervay-Hague, J., Brutkiewicz, R.R. A Thr-Ser dual residue motif in the cytoplasmic tail of human CD1d is important for the down-regulation of antigen presentation following an HSV-1 infection. Immunology 140:191-201, 2013. PMCID: PMC3784165.
- Gourapura, R.J., Khan, M.A., Gallo, R.M., Shaji, D., Liu, J., Brutkiewicz, R.R. Forming a complex with MHC class I molecules interferes with mouse CD1d functional expression. PLoS ONE 8(8):e72867, 2013. PMCID: PMC3756957.
- Walline, C., Deffit, S., Wang, N., Guindon, L., Crotzer, V., Liu, J., Hollister, K., Eisenlohr, L., Brutkiewicz, R.R., Kaplan, M., Blum, J. Virus-encoded ectopic CD74 enhances poxvirus vaccine efficacy. Immunology 141:531-539, 2014. PMCID: PMC3956427.
- Bailey, J.C., Iyer, A.K., Renukaradhya, G.J., Lin, Y., Nguyen, H., Brutkiewicz, R.R. Inhibition of CD1d-mediated antigen presentation by the TGF-b/Smad signaling pathway. Immunology 143(4):679-691, 2014. PMCID: PMC4253516.
- Zimmerer, J.M., Swamy, P., Sanghavi, P.B., Wright, C.L., Elzein, S.M., Brutkiewicz, R.R., Bumgardner, G.L. Critical role of NKT cells in posttransplant alloantibody production. Am. J. Transplantion 14(11):2491-2499, 2014. PMCID: PMC4207222.
- Iyer, A.K., Liu, J., Gallo, R.M., Kaplan, M.H., Brutkiewicz, R.R. STAT3 promotes CD1dmediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis. Immunology (in press), 2015. PMCID: pending.
- B.S., 1981: Michigan State University
- Ph.D., 1993: University of Massachusetts Medical Center
- PostDoctoral, 1993-1998: National Institutes of Health