Study of the mechanisms of generation of Regulatory T cells from naive t cells: the role of adenosine signaling

Abstract

Regulatory T cells (Tregs) are essential to maintain peripheral tolerance, preventing autoimmune diseases and limiting in chronic inflammatory diseases. Furthermore, these cells play a critical role in the control of transplant rejection. Different protocols showed that it is possible to obtain Tregs from naive T cells in vitro CD4+. For this, the consensus is that TGF-beta and interleukin-2 (IL-2) are able to direct the naive CD4+ T cells to become regulatory after antigenic stimulation (anti-CD3/CD28). Furthermore, the use of other stimulus such as trans retinoic acid (atRA) and rapamycin are capable of promoting this generation. Recently our group has noted that in immunomodulation of T lymphocytes by mesenchymal stromal cells (MSCs) these were able to produce adenosine (ADO) which, in turn participates in the immunoregulation process. Other studies indicate that MSCs suppressed the proliferation of T cells for the generation of Tregs and MSCs induce the generation of Tregs via the TCR down-regulation of the pathway and the AKT-mTOR pathway. Evidence suggests that ADO can act negatively regulating mTOR pathway. Therefore, it is believed that the ADO can participate in the generation of Tregs process by modulating the mTOR pathway. Furthermore, recent studies indicate that activation of adenosine receptors, more specifically A2b with agonists, leads to increased production of Treg cells, whereas the use of agents antagonists of these receptors leads to decreased differentiation of Treg. However, these studies demonstrate the generation of Treg from naive T cells of mice. Aiming to obtain improvements in our protocols generation of Tregs from naive human T cells, the main objective of this project is to evaluate the participation of ADO agonists and antagonists on the induction of regulatory T cells generated in vitro (iTreg) by activating CD4+ T cells freshly isolated from human umbilical cord blood naive cells. Seen the great importance of Tregs in immune context, the efficient production of Tregs in vitro is of fundamental importance for the development of new therapeutic protocols for the treatment of autoimmune diseases and combating transplant rejection. (AU)