Faculty Bibliography

Neutrophils possess a diverse arsenal of enzymatic and chemical weapons that can inflict damage upon pathogens and host cells alike. Most tumors harbor neutrophils even from the earliest stages of progression (premalignancy), wherein these weapons could, in theory, either kill a tumor cell or enhance its malignant potential via mutagenesis. However, the interaction between neutrophils and premalignant tumor cells has not been well characterized. To this end, we utilized a mouse model of endometrial carcinoma with defined stages of premalignancy and malignancy that faithfully represent human endometrial cancer progression. We observed robust neutrophil infiltration within premalignant lesions, accompanied by elevated expression of G-CSF, Il1a, Il1b and CXCR2 ligands. Blockade of G-CSF signaling substantially reduced tumor-associated neutrophil numbers and had profound and contrasting effects on tumor growth versus progression. Neutrophil-depleted lesions were larger and contained an increased number of proliferating tumor cells, but concomitantly showed less dysplasia and a reduced amount of DNA damage within tumor cells. Additionally, neutrophil recruitment into premalignant lesions relied heavily upon IL-1 signaling to induce the expression of G-CSF and CXCR2 ligands. These data establish a double-edged sword paradigm for neutrophils in the premalignant tumor microenvironment as agents of both tumor cell death and malignant potentiation

Understanding the function of T cells at the maternal-fetal interface remains one of the most difficult problems in reproductive immunology. A great deal of work over the last two decades has led to the view that the T cells that populate the decidua have important roles in both normal and pathological pregnancies, but the exact nature of these roles has remained unclear. Indeed, the old assumption that decidual T cells are uniformly threatening to fetal survival because the placenta is fundamentally an 'allograft' has given way to the idea that different T cell subsets contribute in different ways to pregnancy success or failure. Accordingly, some T cells are thought to protect the placenta from immune rejection and facilitate embryo implantation, while others are thought to contribute to pregnancy pathologies such as preeclampsia and spontaneous abortion. Here, we review the current state of information on the behavior of decidual T cells with a focus on both mouse and human studies, and with an emphasis on the many unresolved areas within this overall emerging framework.

Work on the mechanisms of fetomaternal tolerance has undergone a renaissance in recent years, and the general outlines of a solution to this long-standing paradox of 'transplantation' immunology have come into view. Here, we discuss several mechanisms, recently described in mice, that either minimize the activation of maternal T cells with fetal or placental specificity, or minimize the possibility that such T cells, if activated, are able to harm the fetus. The T cell response to antigens expressed by the conceptus serves as a paradigm for the study of tissue-specific immune tolerance and is relevant to the pathogenesis of immune-mediated pregnancy complications.

The immune cells that reside at the interface between the placenta and uterus are thought to play many important roles in pregnancy. Recent work has revealed that the composition and function of these cells are locally controlled by the specialized uterine stroma (the decidua) that surrounds the implanted conceptus. Here, I discuss how key immune cell types (natural killer cells, macrophages, dendritic cells, and T cells) are either enriched or excluded from the decidua, how their function is regulated within the decidua, and how they variously contribute to pregnancy success or failure. The discussion emphasizes the relationship between human and mouse studies. Deeper understanding of the immunology of the maternal-fetal interface promises to yield significant insight into the pathogenesis of many human pregnancy complications, including preeclampsia, intrauterine growth restriction, spontaneous abortion, preterm birth, and congenital infection.

Maternal immune tolerance towards the fetus and placenta is thought to be established in part by pathways that attenuate T cell priming to antigens released from the placenta into maternal blood. These pathways remain largely undefined and their existence, at face value, seems incompatible with a mother's need to maintain a functional immune system during pregnancy. A particular conundrum is evident if we consider that maternal antigen presenting cells, activated in order to prime T cells to pathogen-derived antigens, would also have the capacity to prime T cells to co-ingested placental antigens. Here, we address this paradox using a transgenic system in which placental membranes are tagged with a strong surrogate antigen (ovalbumin). We find that although a remarkably large quantity of acellular ovalbumin-containing placental material is released into maternal blood, splenic CD8 T cells in pregnant mice bearing unmanipulated T cell repertoires are not primed to ovalbumin even if the mice are intravenously injected with adjuvants. This failure was largely independent of regulatory T cells, and instead was linked to the intrinsic characteristics of the released material that rendered it selectively non-immunogenic, potentially by sequestering it from CD8alpha(+) dendritic cells. The release of ovalbumin-containing placental material into maternal blood thus had no discernable impact on CD8 T cell priming to soluble ovalbumin injected intravenously during pregnancy, nor did it induce long-term tolerance to ovalbumin. Together, these results outline a major pathway governing the maternal immune response to the placenta, and suggest how tolerance to placental antigens can be maintained systemically without being detrimental to host defense.

Sponsored by the New York Academy of Sciences and Cincinnati Children's Hospital Medical Center, with support from the National Institute of Environmental Health Sciences (NIEHS), the National Institute on Drug Abuse (NIDA), and Life Technologies, "Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Preterm Birth" was held on June 11-12, 2012 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, and highlighted the need for specialized testing of drugs, consumer products, and industrial chemicals, with a view to the unique impacts these can have during gestation. Speakers went on to discuss many other factors that affect prenatal development, from genetics to parental diet, revealing the extraordinary sensitivity of the developing fetus.

The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell-attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.

OBJECTIVES/SPECIFIC AIMS: Inflammation can both inhibit and promote carcinogenesis by eliciting immunogenic T-cell responses to tumor antigens while simultaneously fostering DNA damage and angiogenesis. Rational use of pro- or antiinflammatory treatments as cancer prophylactics and therapeutics, however, is currently limited by an incomplete understanding of how each component of the inflammatory tumor microenvironment combats or enhances tumor growth. Most critically, the cellular and molecular circuitry that drives inflammation during premalignancy remains largely undefined, in part due to a lack of tractable animal models. METHODS/STUDY POPULATION: We have addressed this issue using an autochthonous mouse model of endometrial carcinoma that has well-defined stages of premalignancy and malignancy. RESULTS/ANTICIPATED RESULTS: Premalignant but not malignant lesions showed robust inflammation, characterized by a massive intraepithelial accumulation of neutrophils, increased expression of IL-23 and COX2, and an increased density of IL-17A-producing lymphocytes - most of which were T cells. Furthermore, T cells infiltrated premalignant lesions prior to neutrophils, while pharmacologic COX2 inhibition abrogated neutrophil accumulation in tumor-bearing uteri. DISCUSSION/ SIGNIFICANCE OF IMPACT: Together, these results suggest a complex interplay between T cells and the IL-23-IL-17A and COX2-prostaglandin signaling axes in orchestrating premalignant inflammation