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Research

Overview

Work in the Erlebacher laboratory lies at the intersection of immunology and developmental biology. In particular, we are interested in how the developmental properties of a tissue influence its ability to mount a successful immune response, and, conversely, how cells of the immune system influence tissue development and remodeling.

The platform for our research is the mouse uterus. Not only does this organ provide, at baseline, a simple mucosal tissue amendable to extensive experimental manipulation, but its ability to accommodate the presence of immunologically foreign tissues during pregnancy (i.e. the fetus and placenta) provides a striking example of how the immunological properties of a peripheral tissue are determined by its anatomical organization and developmental plasticity. The immunological protection afforded the fetus and placenta by the uterus is obviously critical to reproductive success, and understanding how this process breaks down will have major implications for clinical disorders of pregnancy. However, we are also interested in how the uterine adaptation to pregnancy finds parallels in the adaptations of the tumor microenvironment that facilitate tumor escape from the immune-mediated destruction, and how the spatial regulation of leukocyte trafficking and differentiation within the uterus contribute towards its developmental response to pregnancy.

Lastly, we are interested in delineating the systemic mechanisms of immunosuppression that operate during pregnancy, and in determining whether these mechanisms can be harnessed to treat autoimmune disease.

Projects in the lab currently include
:

1) Dendritic cell (DC) surveillance of the maternal/fetal interface and of the tumor-bearing non-pregnant uterus. Upon embryo implantation, the uterus undergoes a stereotypical tissue reaction called decidualization. This reaction generates the decidua, a specialized stromal tissue that encases the fetus and placenta. In a recent study (Collins et al., 2009), we showed that uterine DCs stationed within the endometrium at the time of implantation become entrapped within the tissue, and thus do not contribute to T cell recognition of fetal/placental antigens in the uterine lymph nodes. We wish to understand the basis of this phenomenon, and whether analogous pathways might attenuate DC surveillance of endometrial carcinomas.

2) Dendritic cell and macrophage homeostasis and function in the pregnant and non-pregnant uterus. As gestation progresses, uterine DCs and macrophages show a marked reduction in tissue density within the decidua, but maintain constant tissue densities within the myometrium, which is the smooth muscle layer that surrounds the decidua. We wish to understand the cellular and molecular basis of this differential regulation of DC and macrophage homeostasis, and in particular whether it lies at the level of precursor cell recruitment from the blood or at the level of the in situ proliferation of mature cells. We also wish to under how myometrial macrophages contribute to the radical hemangiogenic and lymphangiogenic remodeling of the uterus that occurs during pregnancy.

3) Regulation of maternal T cell responses during pregnancy by hematogenously shed placental microparticles. In recent work, we have found that the immune response to membranous microparticles shed from the placenta is highly tolerogenic (McCloskey et al., submitted). We are interested in understanding why this is the case, and whether these microparticles can be used to treat autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus.

4) T cell behavior at the maternal/fetal interface. Remarkably, selective, antigen-specific fetal loss does not occur in pregnant mice known to contain activated cytotoxic T cells (CTLs) with anti-fetal/placental specificity (Erlebacher et al., 2007). We wish to understand the basis of this "effector phase" tolerance towards the fetus, and whether it might be due to the specialized characteristics of the decidua that curtail CTL trafficking and/or CTL function.

Relevant Publications

Erlebacher A. Immune surveillance of the maternal/fetal interface: controversies and implications. Trends Endocrinol Metab. 2010;21:428-434. Cited in Pubmed; PMID 20304670. doi: 10.1016/j.tem.2010.02.003. PMCID: PMC2892024.

Collins MK, Tay CS, Erlebacher A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Invest. 2009 Jul;119(7):2062-73. doi: 10.1172/JCI38714. PMCID: PMC2701881 (see associated Commentary on pp. 1854-1857; the paper was also highlighted in the August 2009 issue of Nat. Rev. Immunol.).

Erlebacher A, Vencato D, Price KA, Zhang D, Glimcher LH. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J Clin Invest. 2007 May;117(5):1399-1411. Cited in Pubmed; PMID 17446933. doi: 10.1172/JCI28214. PMCID: PMC1849983.