Summary Gender bias and the role of sex hormones in autoimmune diseases are well established. In specific pathogen-free (SPF) non-obese diabetic (NOD) mice, females have 1.3–4.4 times higher incidence of Type 1 diabetes (T1D). Germ-free (GF) mice lost the gender bias (female/male ratio 1.1–1.2). Gut microbiota differed in males and females, a trend reversed by male castration confirming that androgens influence gut microbiota. Colonization of GF NOD mice with defined microbiota revealed that some, but not all, lineages overrepresented in male mice supported a gender bias in T1D. Although, protection of males did not correlate with blood androgen concentration, hormone-supported expansion of selected microbial lineages may work as a positive feedback mechanism contributing to the sexual dimorphism of autoimmune diseases. Gene expression analysis suggested pathways involved in protection of males from T1D by microbiota. Our results favor a two-signal model of gender bias, in which hormones and microbes together trigger protective pathways.

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BackgroundFoxp3 has been suggested to be a standard marker for murine Tregs whereas its role as marker for human Tregs is controversial. While some reports have shown that human Foxp3+ T cells had no regulatory function others have shown their role in the inhibition of T cell proliferation.MethodsT cell activation was performed by means of brayostatin-1/ionomycin (B/I), mixed lymphocyte reaction (MLR), and CD3/CD28 activation. T cell proliferation was performed using BrdU and CFSE staining. Flow cytometry was performed to determine Foxp3 expression, cell proliferation, viabilities and phenotype analyses of T cells.ResultsBoth CD4+ and CD8+ T cells expressed Foxp3 upon activation in vitro. Expression of Foxp3 remained more stable in CD4+CD25+ T cells compared to that in CD8+CD25+ T cells. The CD4+CD25+Foxp3+ T cells expressed CD44 and CD62L, showing their effector and memory phenotypes. Both FoxP3- responder T cells and CD4+FoxP3+ T cells underwent proliferation upon CD3/CD28 activation.ConclusionExpression of Foxp3 does not necessarily convey regulatory function in human CD4+CD25+ T cells. Increased FoxP3 on CD44+ effector and CD44+CD62L+ memory T cells upon stimulation suggest the activation-induced regulation of FoxP3 expression.

Myeloid-derived suppressor cells (MDSCs) are primarily recognized for their immunosuppressive properties in malignant disease. However, their interaction with other innate immune cells and their regulation of immune responses, such as in parasitic infection, necessitate further characterization. We used our previously published mouse model of MDSC accumulation to examine the immunoregulatory role of MDSCs in B16 melanoma metastasis and Nippostrongylus brasiliensis infection. In this study, we demonstrate that the activity of MDSCs is dependent on the immune stimuli and subset induced. Monocytic MDSCs predictably suppressed antitumor immune responses but granulocytic MDSCs surprisingly enhanced the clearance of N. brasiliensis infection. Intriguingly, both results were dependent on MDSC interaction with mast cells (MCs), as demonstrated by adoptive-transfer studies in MC-deficient (KitWsh/Wsh) mice. These findings were further supported by ex vivo cocultures of MCs and MDSCs, indicating a synergistic increase in cytokine production. Thus, MCs can enhance both immunosuppressive and immunosupportive functions of MDSCs.

Background Although many retrospective studies suggest resection of the primary tumor improves survival in metastatic breast cancer, animal studies suggest resection induces metastasis. Moreover, there has been no critical evaluation of how well animal studies actually model metastatic breast cancer. We utilized our newly established orthotopic cancer implantation under direct vision model to evaluate the hypothesis that primary tumor resection improves survival in metastatic breast cancer by reduction of overall tumor burden and improved immune responsiveness. Methods Murine mammary adenocarcinoma 4T1-luc2 cells that can be visualized by bioluminescence were implanted orthotopically into Balb/c mice under direct vision. Resection of the primary tumors at Days 6, 10, and 28 were compared to sham resection of the contralateral normal mammary gland and observation alone. Tumor burden was quantified by bioluminescence. Tumor draining lymph nodes were identified by intradermal injection of lymphazurin, and primary tumors, lymph nodes and lungs were examined pathologically. Kaplan-Meier survival analyses were performed. Splenocyte myeloid derived suppressor cells (MDSCs) and CD4 or CD8 single positive T lymphocytes were quantified by flow cytometry. Results Tumors invaded locally, metastasized to regional lymph nodes, and then to distant organs, with subsequent mortality. Surgical stress increased tumor burden only transiently without affecting survival. When primary tumor resection decreased overall tumor burden substantially, further growth of metastatic lesions did not increase overall tumor burden compared to observation and survival was improved, which was not the case when resection did not significantly reduce overall tumor burden. Decreasing overall tumor burden through resection of the primary tumor resulted in decreased splenic MDSC numbers and increased CD4 and CD8 cells, suggesting the potential for an improved immunological response against cancer. Conclusions Decreasing overall tumor burden through resection of the primary breast tumor decreased MDSCs, increased CD4 and CD8 cells, and improved survival.