Encephalitogenic T CD4+ cells build a cytotoxic profile during the evolution of experimental autoimmune encephalomyelitis and become CD8alphabeta+

Author(s)

Guilherme Antonio Dutra Morais

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2015-08-27

Examining board members

Alessandro dos Santos Farias; Mariana Lazarini; Rodolfo Thomé

• Advisor: Alessandro dos Santos Farias

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a widely accepted animal model of Multiple Sclerosis (MS) and has been used to study the pathophysiology of the disease. EAE was first considered a Th1 cell mediated pathology. Immune responses developed after immunization with myelin antigens for EAE induction revealed IFN?-producing cells domination in the CNS of animals with the disease. However, IFN?-deficient mice were not resistant, but were instead more susceptible to EAE. It has put under doubts the role of IFN? and, consequently, the role of Th1 cells on the EAE pathogenesis. As an alternative for Th1 subset it was proposed the Th17 subset. After its discovery, Th17 subset has been shown to perform an important role during EAE and other autoimmune pathologies. Today it is accepted that Th1 and Th17 cells present a synergic role during EAE development. Interestingly, it seems that Th17 cells present plasticity during the course of EAE. It was shown that autoagressive Th17 cells shut down the IL-17 expression when reach the CNS and start to produce IFN?. Therefore, it is possible that in the EAE pathology, both IL-17 and IFN? are, at least in part, produced by the same source. Despite both Th1 and Th17 subtypes present proinflammatory activity, it is not completely clear how these cells, classically regarded as a helper, would be able to initiate the disease when adoptively transferred to health animals. In this work we¿ve shown that T CD4+ cells can express cytotoxic associated molecules. It was observed that transcription factors (Runx3 and Eomes) are involved on IFN? production in Th1 cells and Granzyme and Perforin in CD8+ T lymphocytes. Maybe these factors can drive a cytotoxic profile that could account for the initial damage mediated by CD4+ cells. T CD4+ IFN? producing lymphocytes found in the CNS upregulated IL-17 and transcription factors associated with the Th17 subset. This expression was higher than solely IL-17 producing cells. Moreover, these lymphocytes presented Granzyme B production. Surprisingly, we found that some CD4+ T lymphocytes can undergo a differentiation and start to express CD8? and CD8? molecules, becoming a double positive cell. Transcription factors associated with lymphocytes intrathymic maturation, Runx3 and ThPok, respectively responsible for transdifferentiation in CD8+ and CD4+ subtypes, are possibly involved in this mechanism. We observed an upregulation of Runx3 expression in T CD4 lymphocytes that started to produce CD8, what isn¿t typical in mature lymphocytes. It was not shown how the pioneer CD4+ encephalitogenic T cells would exert its effector function. Moreover, the direct cytotoxic ability of these cells remain to be evaluated. Despite this, this work contributed to the elucidation of the disease mechanisms and this subset of cells can be promising to account for future therapies to treat MS (AU)

• FAPESP's process: 13/10637-6 - Citotoxity activity of CD4+ encephalitogenic lymphocytes in Experimental Autoimmune Encephalomyelitis
• Grantee: Guilherme Antonio Dutra Morais
• Support Opportunities: Scholarships in Brazil - Master