Action of Wnt/²-catenin agonists in murine CD4+ T cells

• Grant number: 12/18634-3
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): January 01, 2013
• Effective date (End): March 25, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Edecio Cunha Neto
• Grantee: Carla Cristine Crude dos Santos
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

CD4+ T cells exert a central role in acquired immunity. Homeostasis and consequent maintenance of these cell numbers are fundamental to immune competence, and especially important for the profund immunodeficiency observed in AIDS patients, characterized by low numbers of CD4+ T cells. Furthermore, the control of differentiation and functional activity of CD4 + effector cell subtypes (Th1, Th2, Th17, Treg, Tfh) are essential for maintaining health, and the imbalance of these cells are associated with various diseases. The canonical Wnt/²-catenin pathway regulates many functions in vertebrates, including cell proliferation, survival, differentiation and migration, as well as morphogenesis and organogenesis. This signaling pathway appears to be important in CD4 + T cell homeostasis and differentiation. Data from our group indicate that human naïve CD4 + T lymphocytes exhibit increased expression of HIG2 gene. This phenomenon is even more pronounced in HIV patients that remain immunocompetent and with elevated numbers of CD4 + T cells (long term nonprogressors or LTNP). We also observed that the protein HIG2 as well as lithium salts, both inducers of Wnt/²-catenin pathway, are able to activate this signaling cascade in human naïve CD4 + T cells, and promote HIG2 expression. . HIG2 itself is able to activate the Wnt/²-catenin pathway in positive feedback loop in naïve CD4 + T cells, and is hence able to induce cell proliferation. We found a negative correlation between HIG2 expression and the number of circulating CD4 + T cells in HIV infected patients. . Together, these results suggest an important role for HIG2 and the Wnt/²-catenin pathway in CD4 + T cell homeostasis. Additionally, this pathway also influences T cells differentiation in peripheral lymphoid tissues. In genetically modified animal models, it was found that intermediates and transcription factors of this pathway can positively or negatively influence the polarization of these cells. The use of Wnt/²-catenin pharmacological agonists, such as lithium salts, has been little exploited as modulators of CD4 + T cell function. In this project, we will evaluate two different parameters in C57BL/6 mice. First, we will analyze the effect of in vivo and in vitro treatment with lithium salts in the activation of the Wnt/²-catenin pathway and in the homeostatic proliferation of peripheral CD4 + T cells. Secondly, we will evaluate the effect of this treatment on functional subsets of CD4 + T cells, by the quantification of these diverse cell types and the different cytokines produced by each subpopulation in various lymphoid tissues. In this way, our main aim is to elucidate in more detail the role of Wnt/²-catenin pathway in the physiology of CD4 + T cells. Furthermore, we may evaluate the immunomodulatory effect of lithium salts, permitted for clinical use for decades, with possible therapeutic implications. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SANTOS, Carla Cristine Crude dos. Role of Wnt/beta-catenin pathway in murine CD4 T cells. 2015. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.