Early responses of Tregs and effector T cells (Teffs

Regulatory T cells (Tregs) play crucial roles in both fetal and tumor development. We recently showed that immunosurveillance by pre-existing CD44hiCD62Llow activated/memory Tregs (amTregs) specific for self-antigens protects emergent tumor cells in mice. This Treg response of a memory type is more rapid than and dominates the anti-tumor response of tumor-specific effector T cells. Here, we report striking similarities between the early Treg responses to embryo and tumor implantation. Tregs are (i) rapidly recruited to uterus-draining lymph nodes and activated in the first days after embryo implantation in both syngeneic and allogeneic matings; (ii) they express the markers of the amTreg subset; and (iii) are at least in part self-antigen-specific, as seen in tumor emergence. Unlike in the tumor emergence setting, however, for which pre-immunization against tumor antigens is sufficient for complete tumor eradication even in the presence of Tregs, Treg depletion is additionally required for high frequencies of fetus loss after pre-immunization against paternal tissue antigens. Thus, amTregs play a major role in protecting embryos in both naïve and pre-immune settings. This role and the ensuing therapeutic potential are further highlighted by showing that Treg stimulation, directly by low-dose interleukin-2 or indirectly by Fms-related tyrosine-kinase-3 ligand, lead to normal pregnancy rates in a spontaneous abortion-prone model.

Human Papillomavirus (HPV) 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions.