CD1D-Restricted T cells and Pregnancy Loss

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DESCRIPTION (provided by applicant): 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.