Innate mechanisms involved in the regulatory T cells collapse during Toxoplasma gondii-induced intestinal inflammation

• Grant number: 14/03249-2
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Effective date (Start): August 01, 2014
• Effective date (End): October 31, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: João Santana da Silva
• Grantee: Murilo Solano Dias
• Supervisor: Yasmine Belkaid
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: National Institutes of Health, Bethesda (NIH), United States
• Associated to the scholarship: 13/15123-0 - Mechanisms involved in cytokine mediated Treg collapse during Toxoplasma gondii-induced gut inflammation, BP.MS

Abstract

The regulatory T cells (Tregs) promote the immune system homeostasis by inhibiting the development of exacerbated responses especially at the sites of high antigen exposure, such as the gastrointestinal (GI) tract. The GI tract-associated immune system needs to tolerate constant exposure to innocuous antigens while simultaneously maintaining the capacity to respond to pathogens. When the intestinal tolerance is lost, the exacerbated inflammation leads to progression of severe lesions in the mucosal tissue, translocation of intestinal contents and, subsequent induction of immunity against commensals. In murine model, the infection with Toxoplasma gondii is associated with the breakdown of the GI tract immunotolerance: C57BL/6 mice succumb to the infection during the acute stage of the disease because of the severe intestinal inflammation and collapse of Tregs, which allow the development of Th1 response, not only specific for the parasite, but also against the microbiota components. On the other hand, BALB/c mice are resistant to the disease and control the inflammation by sustaining the population of Tregs. Our preliminary data showed that the development of intestinal inflammation and collapse of Tregs in T. gondii-infected C57BL/6 mice is associated with the high production of IL-6. Furthermore, IL-6-deficient C57BL/6 mice became resistant to the disease and sustain the Tregs over the course of infection. The depletion of Tregs in the IL-6-/- mice made them susceptible to the infection, suggesting that the increase on IL-6 production during T. gondii infection negatively influences the Treg maintenance. Therefore, IL-6-mediated collapse of Tregs impairs the control of Th1 immune response resulting in the severe inflammatory response in the gut. On the opposite way, BALB/c mice do not produce higher levels of IL-6 after infection. IL-6 production might be triggered by innate immune receptors, such as TLRs (Toll Like receptors) on macrophages, inflammatory monocytes and dendritic cells (DC). It has been described that during the oral infection with T. gondii, intestinal bacterial antigens activate TLRs 2, 4 and 9, contributing to the inflammation. In parallel, the parasite is able to activate TLR11 and TLR12. Thus, stimulation of TLRs triggers the production of various pro-inflammatory cytokines, which could interfere in the fate of Tregs and the adaptive immune response. In this context, our aim is to determine the mechanisms involved in the collapse of Tregs during the T. gondii infection, focusing on the role of IL-6 induced via receptors of the innate immunity in macrophages or DCs. Since the IL-6 production by innate cells is an early event during the infection and seems to define the fate of Tregs, understanding the mechanisms mediating the differential production of IL-6 between resistant and susceptible mice will collaborate for understanding the pathogenesis of intestinal inflammatory disorders. (AU)