Complex cellular and molecular interactions that take place in inaccessible tissue microenvironment are at the heart of critical regulatory processes which determine whether immune responses occur and, if they do, their eventual outcome as immunity to foreign pathogens, tolerance, autoimmunity, or rejection of tissue allografts. The goal of the proposed study is to examine a novel immunoregulatory mechanism in which cells expressing the enzyme indolamine 2,3 dioxygenase (IDO) regulate T cell responses in vivo. IDO enzyme catabolizes the essential amino acid L-tryptophan and is encoded by an interferon-gamma-inducible gene expressed by macrophages that suppress T embryo loss a few days after blastocyst implantation in mice carrying allogeneic conceptus. Inhibition of IDO activity has no effect on development of syngeneic conceptus. Embryo loss does not occur in mothers carrying a defective recombinase activating gene (RAG-1-/- mice), which have no lymphocytes, and is provoked by a single paternally-inherited MHC class I alloantigen, H-2K/b, when IDO activity is blocked. These data suggest that cells expressing the IDO gene, which is expressed in decidual tissues from early gestation times, moderate maternal lymphocyte responses directed against paternally- inherited fetal MHC alloantigens. Our hypothesis is that cells expressing IDO suppress maternal lymphocyte responses directed against allogeneic conceptus. We will identify cells that express IDO in vivo and the effect that interactions between T cells and cells expressing IDO have on T cell phenotype and function (Aim 1). We will identify fetal alloantigens that provoke lymphocyte mediated embryo loss and effector mechanisms that mediate embryo loss (Aim 2). Using existing lines of T cell receptor and H-2K/b transgenic mice we will examine how cells expressing IDO interact with T cells in allogenic conceptus leading (a) to embryo loss when IDO activity is blocked (Aim 2) and (b) to maternal T cell tolerance to paternally-inherited H-2K/b alloantigen when IDO activity is not blocked (Aim 3). To facilitate this study we will also examine how T cells induced cells to express IDO in vitro and in vivo following adoptive transfer of autoreactive T cells from TCR transgenic mice to H-2K/b-transgenic mice. From these studies we will test the validity of our hypothesis and, if verified, demonstrate that depletion of L-tryptophan is a fundamental immunoregulatory mechanism that protects developing embryos from maternal lymphocytes. In the long term our aim is to use knowledge gained from these studies to examine whether this mechanism can be adapted for therapeutic application to suppress autoreactive T cell responses and moderate T cell responses to tissue allografts.
| Li, Lingqian; Huang, Lei; Lemos, Henrique P et al. (2012) Altered tryptophan metabolism as a paradigm for good and bad aspects of immune privilege in chronic inflammatory diseases. Front Immunol 3:109 |
| Mellor, Andrew L; Munn, David H (2011) Physiologic control of the functional status of Foxp3+ regulatory T cells. J Immunol 186:4535-40 |
| Medzhitov, Ruslan; Shevach, Ethan M; Trinchieri, Giorgio et al. (2011) Highlights of 10 years of immunology in Nature Reviews Immunology. Nat Rev Immunol 11:693-702 |
| Baban, Babak; Chandler, Phillip R; Johnson 3rd, Burles A et al. (2011) Physiologic control of IDO competence in splenic dendritic cells. J Immunol 187:2329-35 |
| Johnson 3rd, Burles A; Kahler, David J; Baban, Babak et al. (2010) B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 107:10644-8 |
| Huang, Lei; Baban, Babak; Johnson 3rd, Burles A et al. (2010) Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int Rev Immunol 29:133-55 |
| Cobbold, Stephen P; Adams, Elizabeth; Farquhar, Claire A et al. (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A 106:12055-60 |
| Baban, Babak; Chandler, Phillip R; Sharma, Madhav D et al. (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475-83 |
| Keskin, Derin B; Marshall, Brendan; Munn, David et al. (2007) Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase. Cell Mol Biol Lett 12:82-102 |
| Baban, Babak; Chandler, Phillip; McCool, Doris et al. (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J Reprod Immunol 61:67-77 |
Showing the most recent 10 out of 20 publications
