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.

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.