Invariant natural killer T cells (iNKT cells) are a fascinating, innate-like T lymphocyte population that recognizes glycolipids presented by CD1d, a class I-like antigen- presenting molecule. Mice deficient for iNKT cells are highly susceptible t infection by inhalation with Streptococcus pneumoniae (S. pneumoniae), a pathogen that is responsible for many deaths worldwide. We have identified glycolipid antigens from S. pneumoniae that activate the T cell antigen receptor (TCR) of iNKT cells, and we have shown TCR-dependent activation of these cells to produce IFN? or IL-17 within hours of infection. While it is established that iNKT cells augment the innate immune response in the lung, there is little information as to how they do this, and if the separate iNKT cell subsets dedicated to IFN? or IL-17 production behave differently.
In aim one, we will use imaging and other technologies to track the iNKT cell response in the lung of infected mice. We will identify the cell types the subsets of iNKT cells interact with, their recruitment and expansion in situ, and their dynamic behavior.
In aim two, we will determine how the innate immune response of myeloid cells and epithelial cells to S. pneumoniae is affected by the absence of iNKT cells, or iNKT cell production of IFN? and/or IL-17. We have shown that the Ig super family member BTLA is important for epithelial innate responses by binding to the TNF super family receptor HVEM. Therefore, also in Aim 2, we will determine if BTLA expression by iNKT cells is required, which would be suggestive of a novel, direct interaction of iNKT cells with epithelial cells. Alternativey, a requirement for BTLA expression by another cell type, combined with data from our intravital imaging studies, would be suggestive of an indirect iNKT- epithelial cell interaction.
In aim three we will identify the cell type(s) that must express CD1d for a protective response to infection using mice with a floxed Cd1d allele. Our hypothesis is that iNKT cells activate diverse elements of innate immunity in the lung, including epithelial cells, and that IFN? and IL-17 producing iNKT cells have non redundant roles in host defense. The results from these studies will provide novel information on the innate immune response in the lung and how iNKT cells modulate this response. The increased understanding of iNKT cell function we will gain may contribute to the improved design of glycolipid adjuvants that stimulate iNKT cells to combat infections.

Public Health Relevance

Streptococcus pneumoniae (S. pneumoniae) causes pneumonia and meningitis and is responsible for many deaths. We are studying natural killer T cells (NKT cells), a type of white blood cell, because mice that lack NKT cells are highly susceptible to S. pneumoniae infection. We will determine how NKT cells protect the host from infection; the resulting knowledge may lead to the development of better adjuvants or substances that improve vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense (IHD)
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Lu, Kristina
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La Jolla Institute
La Jolla
United States
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Engel, Isaac; Seumois, Grégory; Chavez, Lukas et al. (2016) Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat Immunol 17:728-39
Crosby, Catherine M; Kronenberg, Mitchell (2016) Invariant natural killer T cells: front line fighters in the war against pathogenic microbes. Immunogenetics 68:639-48
Pei, Bo; Zhao, Meng; Miller, Brian C et al. (2015) Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation. J Immunol 194:5872-84
Birkholz, Alysia M; Girardi, Enrico; Wingender, Gerhard et al. (2015) A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-? Production. J Immunol 195:924-33
Birkholz, Alysia M; Howell, Amy R; Kronenberg, Mitchell (2015) The Alpha and Omega of Galactosylceramides in T Cell Immune Function. J Biol Chem 290:15365-70