Brutkiewicz Lab

The research lab of Randy R. Brutkiewicz, PhD studies immune evasion by microbial pathogens and tumors, as well as the regulation of antigen presentation by various signal transduction pathways, in both innate and adaptive immune responses.

Investigations are mainly focused on the host’s innate anti-microbial and anti-tumor immune responses, especially, CD1d and MR1 molecules, cell surface glycoproteins structurally related to major histocompatibility complex (MHC) class I molecules. These molecules present lipid antigens to Natural Killer T (NKT) cells and microbial vitamin B-derived metabolites to mucosal associated invariant T (MAIT) cells, respectively.

Active Research

Recently, the laboratory showed that the presentation of microbial antigens by MR1 to MAIT cells is facilitated by the activation of signals via TLR9. 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 other microbial pathogens. Moreover, this will be very useful in the treatment of various hematopoietic tumors, in which the reciprocal regulation of antigen presentation by mitogen-activated protein kinases (described below) is also observed.

Work on the NKT cell arm of the host’s innate antitumor response has revealed differences between different CD1d+ B and T cell tumors. 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.

Signal Transduction Pathways

Currently, the Brutkiewicz Lab is focused on how signal transduction pathways can regulate antigen presentation in both innate (i.e., CD1d and MR1) and adaptive (e.g., MHC class II) immune responses. 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. Furthermore, 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.

Research Funding

National Institutes of Health, National Cancer Institute, “Immune Evasion by Multiple Myeloma:  Role of the Rho Kinase Signaling Pathway”, R01 CA161178 ($207,500 annual direct costs); Principal Investigator:  Randy R. Brutkiewicz, Ph.D.  (04/01/12 – 03/31/18).

Recent Publications

Liu, J., Brutkiewicz, R.R.  The Toll-like receptor 9 signaling pathway regulates MR1-mediated bacterial antigen presentation in B cells.  Immunology 152:232-242, 2017.  PMCID:  PMC5588774.

Webb, T.J., Carey, G.B., East, J.E., Sun, W., Bollino, D.R., Kimball, A.S., Brutkiewicz, R.R.  Alterations in cellular metabolism modulate CD1d-mediated NKT cell responses.  Pathogens and Disease 74(6). pii: ftw055. doi: 10.1093/femspd/ftw055, 2016.  PMCID:  in process.

Liu, J., Gallo, R.M., Duffy, C., Brutkiewicz, R.R.  A VP22-null HSV-1 is impaired in inhibiting CD1d-mediated antigen presentation.  Viral Immunol. 29:409-416, 2016.  PMCID:  PMC5031099.

Brutkiewicz, R.R.  Cell signaling pathways that regulate antigen presentation.  J. Immunol.  197:2971-2979, 2016.  PMCID:  PMC5119928.

Iyer, A.K., Liu, J., Gallo, R.M., Kaplan, M.H., Brutkiewicz, R.R.  STAT3 promotes CD1d-mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis.  Immunology 146(3):444-455, 2015.  PMCID:  PMC4610633.

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-/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.

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.

 

Faculty Research Team

Randy R. Brutkiewicz, PhD

Randy R. Brutkiewicz, PhD

Professor of Microbiology & Immunology
Jianyun (Jean) Liu, PhD

Jianyun (Jean) Liu, PhD

Assistant Research Professor of Microbiology & Immunology