Autocrine IFNγ Controls the Regulatory Function of Lymphoproliferative Double Negative T Cells

<div><p>TCRαβ⁺ CD4⁻CD8⁻NK⁻ double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4⁺ T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.<em>lpr</em> (B6.<em>lpr</em>) DN T cells. B6.<em>lpr</em> DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4⁺ T cells responding to alloantigen stimulation both <em>in vitro</em> and <em>in vivo</em>. Autocrine IFNγ signaling was required for sustained B6.<em>lpr</em> DN T cell IFNγ secretion <em>in vivo</em> and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.<em>lpr</em> DN T cells permitted lysis of activated CD4⁺ T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.<em>lpr</em> DN T cells.</p>