Tolerance Through Induction of Regulatory T Cells

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

Regulatory CD4 T cells (Treg) play a key role in the prevention of autoimmunity and maintenance of[unreadable] allograft tolerance. For example, in the gut, Treg prevent effector T cells from mounting a destructive[unreadable] inflammatory response to a myriad of non-pathogenic bacterial antigens. Natural Treg arise in the thymus[unreadable] and exhibit a CD45RBLo phenotype characteristic of activated cells. Treg can also be induced, for example,[unreadable] by activation of peripheral T cells in vitro in the presence of Antigen Presenting Cells plus cytokines or in vivo[unreadable] by oral antigen. However, it is generally unclear whether these Treg primarily arise as an outgrowth of preexisted[unreadable] Treg within the CD45RBLo population vs. de novo generation from naive CD45RBHi effector cells.[unreadable] Recent findings suggest that the latter is possible, at least in specialized circumstances. If Treg can be[unreadable] induced de novo, we can delineate the signals involved in differentiation from effector cells to Treg. This[unreadable] would have important clinical implications since this conversion represents a shift in the immune response[unreadable] from immunity to tolerance. Moreover, CTLA-4 upregulation is accompanied by induction of Foxp3, a[unreadable] transcription factor key for Treg development. These changes occur in vitro in isolated T cells and in the[unreadable] absence of T cell activation. Preliminary data reveal that this mAb can prevent IBD caused by CD45RBHI[unreadable] effectors by inducing Treg function, suggesting that alpha-CD45RB initiates de novo conversion of effector cells[unreadable] into Treg in the absence of T cell activation.[unreadable] In Project 2 we aim to determine the mechanism(s) of action of these novel Treg and delineate signals[unreadable] leading to Foxp3 and CTLA-4 induction. This is central to the theme of this PPG, which aims to define[unreadable] peripheral mechanism of tolerance.[unreadable] In Aim 1, we will define the mechanisms by which de novo Treg prevent IBD. In addition to secretion of[unreadable] suppressive cytokines we hypothesize that they inhibit both APCs and T effector cells through CTLA-4/B7[unreadable] interactions. We will compare the role of CTLA-4/B7 and Foxp3 expression by both induced and natural[unreadable] Treg. Since only a subpopulation of alpha-CD45RB -treated cells expresses CTLA-4, in Aim 2 we will define[unreadable] surface markers that accompany cytoplasmic CTLA-4 expression that can further identify regulatory cells[unreadable] within the population. In Aim 3, we will define the signaling pathways that lead to Treg induction.[unreadable] These studies will provide novel insight into the immunobiology of Treg and the pathways leading to their[unreadable] induction. In turn, this will provide new targets for tolerance induction and the prevention of autoimmunity[unreadable] and transplant rejection. Project 2 integrates with other projects in this PPG on multiple levels.[unreadable]