STAT1 gene deficient mice develop accelerated breast cancer growth and metastasis which is reduced by IL-17 blockade.

Signal transducer and activator of transcription 1 (STAT1) mediates interferon gamma signaling which activates the expression of various genes related to apoptosis, inflammation, cell cycle and angiogenesis. Several experimental and clinical studies have investigated the role of STAT1 in primary tumor growth in breast cancer; however, its role in tumor metastasis remains to be determined. To determine the role of STAT1 in breast cancer metastasis, we analyzed growth and metastasis in WT or STAT1-/- mice orthotopically implanted with metastatic 4T1.2 cells. Primary tumor development was faster in STAT1-/- mice and these mice developed significantly bigger primary tumors and displayed more lung metastasis compared with WT counterparts. STAT1-/- mice showed elevated Ly6G+CD11b+ granulocytic MDSC infiltration in their primary tumors and spleens with concomitant upregulation of Mmp9 and Cxcl1 expression in tumors compared with WT counterparts. Blockade of IL-17A in primary tumor-bearing STAT1-/- mice suppressed accumulation of Ly6G+CD11b+ cells and markedly reduced lung metastasis. These data show that STAT1 is an important suppressor of primary breast tumor growth and metastasis. Importantly, we found anti-IL-17 treatment can rescue STAT1 deficient animals from developing exacerbated metastasis to the lungs which could be important for immunotherapies for immunocompromised breast cancer patients.

Transgenic T cell-specific expression of CXCR3 enhances splenic and hepatic T cell accumulation but does not affect the outcome of visceral leishmaniasis.

The outcome of visceral leishmaniasis, caused by parasite Leishmania donovani, depends on the recruitment of leishmanicidal Th1 cells. Chemokine receptor CXCR3, preferentially expressed by Th1 cells, is critical for migration of these T cells during infection. During chronic VL, there is a decrease in the presence of CXCR3-expressing CD4+ T cells in the spleen, which is associated with high parasitic burden in this organ. We therefore examined whether T cell-specific expression of CXCR3 in mice (CXCR3Tg) would promote resistance to VL. L. donovani infected CXCR3Tg mice showed increased accumulation of T cells in the spleens compared to WT littermates (CXCR3+/+). However, CXCR3+ T cells from CXCR3Tg mice showed low CD69 expression and these mice developed fewer granulomas. Additionally, both groups of mice showed similar cytokine profiles and parasitic burdens during the course of infection. In summary, although T cell-specific expression of CXCR3 promoted the accumulation of CXCR3-expressing T cells during L. donovani infection, this did not enhance resistance to VL.

STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity.

STAT4 is critical for the production of IFN-γ during the generation of Th1 immune responses. We investigated the role of STAT4 in mediating Th1-inducing activity of a vaccine adjuvant monophosphoryl lipid A (MPL-A) using the standard antigen ovalbumin (OVA) in STAT4KO mice. Our results show that splenocytes from STAT4KO mice displayed lower OVA-specific T-cell proliferation and IL-2 production compared with wild-type (WT) mice. Further, IFN-γ production was diminished in STAT4KO-derived splenocytes but the levels of IL-12 and TNF-α were similar compared with WT mice. Interestingly, STAT4 deficiency also led to a decrease in IL-10 and Th2 cytokines such as IL-4 and IL-13 upon MPL-A immunization, although IL-17 production was similar between WT- and STAT4KO-derived splenocytes. Our observations for defective Th1 and Th2 responses in STAT4KO mice were further supported by the low levels of Th1-associated IgG2a and Th2-associated IgG1 in the sera of these mice. Taken together, our results show that STAT4 plays a critical role in mediating both Th1 and Th2 responses upon immunization with MPL-A. Our study provides a better understanding of how MPL-A mediates T-cell activation which will be critical for future vaccine development.

IL-17A promotes susceptibility during experimental visceral leishmaniasis caused by Leishmania donovani.

Leishmania donovani is an intracellular parasite that infects professional phagocytes and causes visceral leishmaniasis (VL). The immune response during VL has been extensively studied in the context of T-helper (Th)1 and Th2 responses. Immunity against this parasite is dependent on IFN-γ production and subsequent macrophage activation, and the Th2 response promotes granuloma formation. The cytokine IL-17A is associated with neutrophilic inflammation. Depletion of neutrophils during experimental VL results in enhanced parasitic loads. Furthermore, although patients resistant to VL showed enhanced levels of IL-17A in circulation, little is known about the role of IL-17A during VL infection. Here, we used IL-17A-deficient mice and IL-17A reporter mice to address the role of IL-17A during VL. IL-17A(-/-) mice were highly resistant to VL infection, showing decreased parasites in the liver and spleen. This unexpected phenotype was associated with enhanced IFN-γ production by T cells and decreased accumulation of neutrophils and monocytes, resulting in reduced number of granulomas. We also found γδ T and Th17 cells as the main IL-17A(+) cells during VL infection. Our data reveal an unexpected role of IL-17A rendering susceptibility against L. donovani by regulating the IFN-γ response and promoting detrimental inflammation.