Role of apoptosis regulatory molecules and DNA demethylating agents on the activation and differentiation of antigen-specific CD8+ T lymphocytes

Abstract

CD8+ T lymphocyte-mediated immune response are crucial to fight intracellular pathogens, including viruses, and tumors. Both entities represent huge challenge to health care, particularly because pathogens and tumors are extremely capable of evading the immune response. Recently, SARS-Cov2-driven pandemic has destabilized the whole world at the health, social and financial point of view. In addition, cancer is the second main cause of death worldwide. Considering this threatening scenario, it is essential to better understand the activation, differentiation and survival mechanisms operating in CD8+ T lymphocyte. The specific function of the effector subsets Tc1, Tc2, Tc9 and Tc17, along with the mechanism that controls their differentiation, remains obscure. Importantly, cell death regulators are known to shape the immune responses, but little is known about the intersection between cell death machineries and the activation/differentiation of T cells. In addition, although DNA methylation regulates gene expression at the CD8 T cell compartment, it is still unclear how demethylating agents modulate the amplitude and quality of CD8 T cell response. We propose to use mice deficient for Fas, FasL or Bim to investigate whether these known lymphocyte death/survival regulators shape the differentiation of CD8+ T cell subpopulations. Also, we will explore whether signals emanating from these molecules modulate naïve and activated CD8+ T cells metabolism, which may impact the differentiation process and their function. Finally, we will explore the effect of DNA demethylating agents on CD8 T cell differentiation. (AU)