Invariant natural killer T (iNKT) cells have been shown to promote resistance to a variety of viral infections. Despite their cytopathic-sounding name, it does not seem that the anti-viral effects of iNKT cells are due to their killing of infected cells. Instead, iNKT cells function as cellular adjuvants that promote anti-viral responses by other lymphocytes, including antigen-specific T cells. iNKT cells are an innate T cell population that is present in all individuals, and that utilizes a conserved TCR that recognizes lipid patterns presented by non-polymorphic CD1d molecules. As a result of these features, iNKT cells can be targeted in genetically diverse human populations using a single therapeutic strategy (e.g. anti-TCR antibodies, synthetic lipid antigens). Thus, iNKT cells could be exploited as a generic (i.e. HLA-independent) strategy to promote anti- viral antigen-specific T cell responses. The goal of this project is to provide mechanistic data that will support the development of human iNKT cells as broad anti-viral agents. The mechanisms involved in human iNKT- mediated adjuvancy in vivo will be investigated using a model of Epstein-Barr virus infection, in which autologous T cells control the degree of virally-driven B cell hyperplasia. Our preliminary studies show that administering iNKT cells at late time points after viral infection is associated with clearance of B- lymphoproliferative masses and with enhanced antigen-specific T cell responses. We will investigate two specific hypotheses about the mechanisms by which iNKT cells mediate these effects: i) by conditioning of monocytic APCs in a way that diminishes their immunosuppressive properties and/or enhances their immunostimulatory features; ii) by directly activating T cells in a way that enables them to overcome suppressive signals.
Aim1 will determine iNKT cell activation requirements;
Aim 2 will ascertain the importance of iNKT cell interactions with monocytic APCs;
Aim 3 will assess the impact of iNKT cells on T cells. These studies will significantly advance our understanding of the cellular and molecular pathways involved in iNKT-mediated adjuvancy, and will thus guide the development of clinical strategies to engage iNKT cells to promote anti-viral immunity.

Public Health Relevance

This project will determine how a population of T lymphocytes that is found in all of us promotes immunity to a viral infection. Understanding how these powerful T cells work will help us to develop broad-based strategies to fight viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI136500-03
Application #
9963115
Study Section
Immunity and Host Defense (IHD)
Program Officer
Kelly, Halonna R
Project Start
2018-08-07
Project End
2023-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Sharma, Akshat; Lawry, Stephanie M; Klein, Bruce S et al. (2018) LFA-1 Ligation by High-Density ICAM-1 Is Sufficient To Activate IFN-? Release by Innate T Lymphocytes. J Immunol 201:2452-2461