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Mechanisms involved in cytokine mediated Treg collapse during Toxoplasma gondii-induced gut inflammation

Grant number: 13/15123-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): December 01, 2013
Effective date (End): April 30, 2015
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:João Santana da Silva
Grantee:Murilo Solano Dias
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):14/03249-2 - Innate mechanisms involved in the regulatory T cells collapse during Toxoplasma gondii-induced intestinal inflammation, BE.EP.MS


The regulatory T cells (Tregs) promote the immune system homeostasis and inhibit the development of exacerbated responses. In the sites of high antigen exposure, such as the gastrointestinal (GI) tract, the immune system establishes a complex non-pathologic relationship with the resident microbiota in order to keep the homeostasis in this site. When the immune tolerance in the GI tract is broken, the exacerbated immune response leads to the development of severe lesions in the mucosal tissue, resulting in a set of diseases known as Inflammatory Bowel Diseases (IBD). In mouse model, the infection with the intracellular parasite Toxoplasma gondii is associated with the breakdown of the GI tract immunotolerance. C57BL/6 mice succumb to the parasite oral infection during the acute stage of the disease due to a severe intestinal inflammation associated with the collapse of Tregs and development of a Th1 response. On the other hand, BALB/c mice strain is resistant to the disease, and maintains 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, C57BL/6 mice deficient in IL-6 production became resistant to the disease and presented high Treg frequency. 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. This phenomenon 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. Generally, the IL-6 production is begins after the activation of innate immunity receptors, such as TLRs (Toll Like receptors). I has been described that during the oral infection with T. gondii, intestinal bacterial antigens activate TLRs 2, 4 and 9, contributing to the development of Th1 immune response. Thus, stimulation of TLRs induces 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-induced breakdown of intestinal mucosal tolerance, focusing on the role of IL-6 induced via receptors of the innate immunity in macrophages or dendritic cells. This model might be important not only for elucidate the mechanisms that control intestinal homeostasis during infection by this parasite, but also to understand the basic phenomena related to the initiation of mucosal responses. (AU)

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