How the fetus and placenta escape rejection during pregnancy likely involves local immune regulation within the maternal decidua, the specialized stromal tissue that surrounds the implanted embryo. Surprisingly, virtually nothing is known about dendritic cells at the maternal/fetal interface, despite the critical importance of this cell type in monitoring peripheral tissue for foreign antigens and controlling subsequent immune responses. Here, we use TCR-transgenic T cell adoptive transfers and a model antigen transgenic system to test whether an antigen expressed exclusively by the fetus and placenta is indeed presented by dendritic cells within the draining lymph nodes of the uterus, and whether the T cell response is tolerogenic or immunogenic (Aim 1). We will then directly characterize the phenotype of decidual dendritic cells and ask whether these cells appropriately mature and emigrate from the uterus under inflammatory and homeostatic conditions (Aim 2). Third, we will characterize the differential recruitment of dendritic cells to the decidua versus the overlying myometrium, and determine the fate of newly recruited progenitor cells (Aim 3). Lastly, we will study how differential chemokine expression in the decidua and myometrium might locally regulate dendritic cell trafficking (Aim 4). An understanding of how dendritic cell behavior is specialized at the maternal/fetal interface might not only help explain how the fetus escapes rejection during pregnancy, a major unsolved question in contemporary immunology, but will likely shed light onto the local regulation of dendritic cell function in peripheral tissues elsewhere in the body. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI062980-01A1
Application #
6965817
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Macchiarini, Francesca
Project Start
2005-05-15
Project End
2005-12-31
Budget Start
2005-05-15
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$348,500
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Rizzuto, Gabrielle; Tagliani, Elisa; Manandhar, Priyanka et al. (2017) Limited Colonization Undermined by Inadequate Early Immune Responses Defines the Dynamics of Decidual Listeriosis. Infect Immun 85:
Nancy, Patrice; Tagliani, Elisa; Tay, Chin-Siean et al. (2012) Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336:1317-21
Tagliani, Elisa; Shi, Chao; Nancy, Patrice et al. (2011) Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J Exp Med 208:1901-16
Tagliani, Elisa; Erlebacher, Adrian (2011) Dendritic cell function at the maternal-fetal interface. Expert Rev Clin Immunol 7:593-602
McCloskey, Megan L; Curotto de Lafaille, Maria A; Carroll, Michael C et al. (2011) Acquisition and presentation of follicular dendritic cell-bound antigen by lymph node-resident dendritic cells. J Exp Med 208:135-48
Erlebacher, Adrian (2011) Strangers no more: uterine NK cell recognition of the placenta in mice. Proc Natl Acad Sci U S A 108:4267-8
Erlebacher, Adrian (2010) Immune surveillance of the maternal/fetal interface: controversies and implications. Trends Endocrinol Metab 21:428-34
Collins, Mary K; Tay, Chin-Siean; Erlebacher, Adrian (2009) Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Invest 119:2062-73
Erlebacher, Adrian; Vencato, Daniela; Price, Kelly A et al. (2007) Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J Clin Invest 117:1399-411