The immune response to pathogens involves a complex interplay between cells that present antigen and those cells that are responsible for effector functions involved in the defense of the host against these foreign invaders. Our laboratory is focused on the interactions between the major histocompatibility complex class Hike molecule, CD1d and a unique population of T cells that are activated by CD1d, NKT cells, in antiviral immunity. We have found that there are alterations in both CD1d molecules and NKT cells following an acute virus infection that may be related (or even independent) events. Various virus-encoded immune evasion molecules (VEIMs), such as the Nef molecule from HIV-1 and the E19 molecule from adenovirus can bind to and substantially decrease the cell surface level of CD1d. This results in a decrease in NKT cell activation and very likely downstream immune effects mediated by other effector cells. Thus, one means by which a viral pathogen could establish a foothold in a host is by targeting the innate antiviral immune response vis-a-vis CD1d molecules and/or NKT cells. There is a selective loss of NKT cells from the liver and other organs following a virus infection, whereas in CD1d1-deficient mice, a virus infection results in higher levels of cytokine production and faster viral clearance. This suggests that the control of the magnitude of an antiviral immune response is CD1d1-dependent. The overall goal of this competitive renewal application is to further understand the role for CD1d molecules and NKT cells in antiviral immunity by building upon our prior studies. Thus, our hypothesis is that certain viruses cause a reduction in the functional expression of CD1d molecules by a direct interaction with VEIMs and/or by altering CD1d1-dependent activation of NKT cells. To test this hypothesis, we have focused on three specific aims. 1. Analyze the mechanisms by which VSV inhibits CDId-mediated antigen presentation, 2. Analyze the functional interaction between HIV-1 Nef and human CD1d, and 3. Study the dynamics of CD1d and NKT cell changes following a virus infection. Increasing our understanding of the roles that CD1d molecules and NKT cells play in the innate antiviral immune response will allow us to exploit this system for the generation of new and novel vaccines, and has clear translational applications to not only this area, but to autoimmunity and cancer as well.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IHD (01))
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Rothermel, Annette L
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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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
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
Walline, Crystal C; Deffit, Sarah N; Wang, Nan et al. (2014) Virus-encoded ectopic CD74 enhances poxvirus vaccine efficacy. Immunology 141:531-9
Liu, Jianyun; Glosson, Nicole L; Du, Wenjun et al. (2013) A Thr/Ser dual residue motif in the cytoplasmic tail of human CD1d is important for the down-regulation of antigen presentation following a herpes simplex virus 1 infection. Immunology 140:191-201
Gourapura, Renukaradhya J; Khan, Masood A; Gallo, Richard M et al. (2013) Forming a complex with MHC class I molecules interferes with mouse CD1d functional expression. PLoS One 8:e72867
Zeng, Melody Yue; Pham, Duy; Bagaitkar, Juhi et al. (2013) An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. Blood 121:3473-83
Walline, Crystal C; Sehra, Sarita; Fisher, Amanda J et al. (2013) Allergic airway disease in mice alters T and B cell responses during an acute respiratory poxvirus infection. PLoS One 8:e62222
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
Broxmeyer, Hal E; Christopherson, Kent; Hangoc, Giao et al. (2012) CD1d expression on and regulation of murine hematopoietic stem and progenitor cells. Blood 119:5731-41

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