The regulation of the antiviral immune response is important for the elimination of a viral pathogen during a primary infection and for the development of protective immunity that will be effective upon re-exposure to that virus in the future. We and others have shown that the innate immune response, specifically, lipid antigen presentation by CD1d to natural killer T (NKT) cells, is an important component of that antiviral immune response. Recently, we demonstrated that a number of signal transduction pathways regulate antigen presentation by CD1d, as well as MHC class II molecules. We further showed that virus infections can disrupt these signaling pathways and alter the intracellular localization of CD1d as a means of immune evasion, vis-?vis CD1d-NKT cell interactions. The CD1d cytoplasmic tail can also be phosphorylated, which can have profound effects on its functional expression. The overall goal of this competitive renewal application is to build upon our prior studies and understand in more detail the mechanisms by which CD1d-mediated antigen presentation is regulated normally and how viruses can affect the ability of cells to present antigen to NKT cells. Our hypothesis is that the Rho GTPase signaling pathway is an important regulator of antigen presentation by CD1d and viruses target Rho-dependent cytoskeletal dynamics in antigen presenting cells to impair their ability to activate NKT cells. To test this hypothesis, we have proposed three specific aims: 1. Determine the role of Rho GTPases in the control of CD1d-mediated antigen presentation;2. Analyze the mechanism(s) by which viruses target the Rho pathway to disrupt antigen presentation by CD1d;3. Analyze Rho GTPase-dependent CD1d and NKT cell dynamics in vivo. Increasing our understanding of the molecular mechanisms that govern antigen presentation by CD1d has applications not only in infectious diseases and vaccine development, but also in cancer and autoimmune diseases as well.
This project will investigate how viruses are able to impair the recognition of infected cells by the immune system. We are focused specifically on changes in the cytoskeleton of these cells upon infection and what controls these changes. Increasing our understanding of immune evasion by viruses has important applications not only to infectious diseases, but also to autoimmunity and cancer.
| Brutkiewicz, Randy R; Yunes-Medina, Laura; Liu, Jianyun (2018) Immune evasion of the CD1d/NKT cell axis. Curr Opin Immunol 52:87-92 |
| Brutkiewicz, Randy R (2016) Cell Signaling Pathways That Regulate Antigen Presentation. J Immunol 197:2971-2979 |
| Iyer, Abhirami K; Liu, Jianyun; Gallo, Richard M et al. (2015) STAT3 promotes CD1d-mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis. Immunology 146:444-55 |
| Bailey, Jennifer C; Iyer, Abhirami K; Renukaradhya, Gourapura J et al. (2014) Inhibition of CD1d-mediated antigen presentation by the transforming growth factor-?/Smad signalling pathway. Immunology 143:679-91 |
| Zimmerer, J M; Swamy, P; Sanghavi, P B et al. (2014) Critical role of NKT cells in posttransplant alloantibody production. Am J Transplant 14:2491-9 |
| Gallo, Richard M; Khan, Masood A; Shi, Jianjian et al. (2012) Regulation of the actin cytoskeleton by Rho kinase controls antigen presentation by CD1d. J Immunol 189:1689-98 |
