CD1 Molecules & NKT Cells in Host Defense

Indiana University Indianapolis, Indianapolis IN

Investigators

Linked publications & trials

Abstract

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-[unreadable]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.