NKT cells are a population of regulatory T cells that is known to be able to potently modulate immune responses. The antigens that control NKT cell activation are lipids and glycolipids presented by CD1d molecules. A remarkable characteristic of NKT cells is that many are autoreactive to self antigens. This allows them to become activated even when there is no foreign antigenic challenge, and may be critical for their endogenous immunoregulatory effects. The auto-antigens recognized by human NKT cells have not been identified, and little is known about how their presentation is regulated. Here we will: i) characterize the endogenous ligands presented by human CD1d molecules, and analyze which ones are antigenic for NKT cells;ii) follow up on our preliminary results, which indicate that an intercellular lipid messenger called lyso- phosphatidylcholine (LPC) that is produced under inflammatory conditions, is a self antigen that can be recognized by many human NKT cells;iii) investigate the cellular and molecular requirements for CD1d-mediated auto-antigen presentation to NKT cells. These studies will provide new information about the lipid characteristics that are important for binding to human CD1d molecules and for recognition by NKT cells, and will explore how NKT cell activation is linked to broader physiological processes of inflammation through recognition of bio-active lipid mediators as self antigens, and will provide critical insights into the mechanisms by which CD1d- mediated auto-antigen presentation is regulated by APCs.

Public Health Relevance

NKT cells are autoreactive regulatory T cells that recognize lipids and glycolipids as antigens presented by CD1d molecules. The molecular identity of the auto-antigens recognized by human NKT cells remains unknown. In this grant we will: i) identify constitutively presented cellular ligands that are recognized by human NKT cells;ii) investigate lipid messengers as putative inducible auto-antigens that may directly link NKT cell activation to inflammatory responses;and iii) analyze cellular and molecular requirements for auto-antigen presentation by CD1d.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074940-04
Application #
8259201
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Miller, Lara R
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$359,141
Indirect Cost
$92,779
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
Felley, Laura E; Sharma, Akshat; Theisen, Erin et al. (2016) Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway. J Immunol 197:2455-64
Xu, Xuequn; Pocock, Ginger M; Sharma, Akshat et al. (2016) Human iNKT Cells Promote Protective Inflammation by Inducing Oscillating Purinergic Signaling in Monocyte-Derived DCs. Cell Rep 16:3273-85
Fox, Lisa M; Miksanek, Jennifer; May, Nathan A et al. (2013) Expression of CD1c enhances human invariant NKT cell activation by α-GalCer. Cancer Immun 13:9
López-Sagaseta, Jacinto; Kung, Jennifer E; Savage, Paul B et al. (2012) The molecular basis for recognition of CD1d/α-galactosylceramide by a human non-Vα24 T cell receptor. PLoS Biol 10:e1001412
Lopez-Sagaseta, Jacinto; Sibener, Leah V; Kung, Jennifer E et al. (2012) Lysophospholipid presentation by CD1d and recognition by a human Natural Killer T-cell receptor. EMBO J 31:2047-59
Wang, Xiaohua; Bishop, Kathleen A; Hegde, Subramanya et al. (2012) Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation. J Exp Med 209:987-1000
Wiemer, Andrew J; Hegde, Subramanya; Gumperz, Jenny E et al. (2011) A live imaging cell motility screen identifies prostaglandin E2 as a T cell stop signal antagonist. J Immunol 187:3663-70
Hegde, Subramanya; Lockridge, Jennifer L; Becker, Yusof A et al. (2011) Human NKT cells direct the differentiation of myeloid APCs that regulate T cell responses via expression of programmed cell death ligands. J Autoimmun 37:28-38
Hegde, Subramanya; Fox, Lisa; Wang, Xiaohua et al. (2010) Autoreactive natural killer T cells: promoting immune protection and immune tolerance through varied interactions with myeloid antigen-presenting cells. Immunology 130:471-83
Fox, Lisa; Hegde, Subramanya; Gumperz, Jenny E (2010) Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation? Microbes Infect 12:1125-33

Showing the most recent 10 out of 13 publications