Successful pregnancy requires the coordinate regulation of the innate and adaptive arms of the immune system. The decidualized endometrium is populated by maternal leukocytes, primarily uterine natural killer (NK) cells, T cells, macrophages, and dendritic cells. The long-term goal of this proposal is to understand the functional relationships among these decidual leukocyte cell subsets and to understand their contribution to the success and maintenance of pregnancy. Semi-invariant NKT (iNKT) cells comprise a novel T cell subset that accumulates in the decidua. iNKT cells recognize CD1d which was recently demonstrated to be expressed on extravillous trophoblast. Our central hypothesis is that decidual iNKT cells can modulate decidual NK cell function, and that this functional relationship may influence pregnancy outcome. Stimulation of iNKT cells in pregnant mice, through administration of the CD1d ligand a-galactosylceramide (aGalCer), induces pregnancy loss in mice. We propose to test our hypothesis by elucidating the mechanism through which iNKT cell activation mediates pregnancy loss in the mouse. Specifically, we propose a model in which aGalCer-stimulated iNKT cells activate CD40+ antigen-presenting cells (APCs). Activated APCs then stimulate decidual NK cells, which ultimately mediate pregnancy loss in a perforin-dependent manner. To test this model we propose the following Specific Aims: (1) to elucidate the iNKT-derived signals required for iNKT cell-mediated pregnancy loss, (2) to elucidate the function and phenotype of the CD40+ intermediate involved in iNKT cell-mediated pregnancy loss, and (3) to elucidate the role and the identity of the cell(s) mediating perforin-dependent pregnancy loss. Completion of these aims may offer insight into the functional contributions of decidual leukocytes to pathological conditions of pregnancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067897-03
Application #
7570046
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Prabhudas, Mercy R
Project Start
2007-03-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
3
Fiscal Year
2009
Total Cost
$372,780
Indirect Cost
Name
University of Vermont & St Agric College
Department
Surgery
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Benoit, Patrick; Sigounas, Vaia Yioula; Thompson, Jenna L et al. (2015) The role of CD1d-restricted NKT cells in the clearance of Pseudomonas aeruginosa from the lung is dependent on the host genetic background. Infect Immun 83:2557-65
Borg, Zachary D; Benoit, Patrick J; Lilley, Graham W J et al. (2014) Polymorphisms in the CD1d promoter that regulate CD1d gene expression are associated with impaired NKT cell development. J Immunol 192:189-99
Liu, Wei; Moussawi, Mohamad; Roberts, Brian et al. (2013) Cross-regulation of T regulatory-cell response after coxsackievirus B3 infection by NKT and ?? T cells in the mouse. Am J Pathol 183:441-9
Huber, Sally Ann; Roberts, Brian; Moussawi, Mohamad et al. (2013) Slam haplotype 2 promotes NKT but suppresses V?4+ T-cell activation in coxsackievirus B3 infection leading to increased liver damage but reduced myocarditis. Am J Pathol 182:401-9
Nagaleekar, Viswas K; Sabio, Guadalupe; Aktan, Idil et al. (2011) Translational control of NKT cell cytokine production by p38 MAPK. J Immunol 186:4140-6
Paveglio, Sara A; Allard, Jenna; Foster Hodgkins, Samantha R et al. (2011) Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure. Am J Respir Cell Mol Biol 44:11-23
Ather, Jennifer L; Ckless, Karina; Martin, Rebecca et al. (2011) Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice. J Immunol 187:64-73
Hodgkins, Samantha R; Ather, Jennifer L; Paveglio, Sara A et al. (2010) NO2 inhalation induces maturation of pulmonary CD11c+ cells that promote antigenspecific CD4+ T cell polarization. Respir Res 11:102
Aktan, Idil; Chant, Alan; Borg, Zachary D et al. (2010) Slam haplotypes modulate the response to lipopolysaccharide in vivo through control of NKT cell number and function. J Immunol 185:144-56
Olson Jr, Chris M; Bates, Tonya C; Izadi, Hooman et al. (2009) Local production of IFN-gamma by invariant NKT cells modulates acute Lyme carditis. J Immunol 182:3728-34

Showing the most recent 10 out of 13 publications