Ifn Gamma Regulates Activated V Delta 2+T Cells Through A Feedback Mechanism Mediated By Mesenchymal Stem Cells

gamma delta T cells play a role in a wide range of diseases such as autoimmunity and cancer. The majority of circulating human gamma delta T lymphocytes express a V gamma 9V delta 2+ (V delta 2+) T cell receptor (TCR) and following activation release pro-inflammatory cytokines. In this study, we show that IFN gamma, produced by V delta 2+ cells, activates mesenchymal stem cell (MSC)-mediated immunosupression, which in turn exerts a negative feedback mechanism on gamma delta T cell function ranging from cytokine production to proliferation. Importantly, this modulatory effect is limited to a short period of time (<24 hours) post-T cell activation, after which MSCs can no longer exert their immunoregulatory capacity. Using genetically modified MSCs with the IFNy receptor 1 constitutively silenced, we demonstrate that IFN gamma is essential to this process. Activated gamma delta T cells induce expression of several factors by MSCs that participate in the depletion of amino acids. In particular, we show that indolamine 2,3-dioxygenase (IDO), an enzyme involved in L-tryptophan degradation, is responsible for MSC -mediated immunosuppression of V delta 2+ T cells. Thus, our data demonstrate that gamma delta T cell responses can be immuno-modulated by different signals derived from MSC.