Double‐negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation

Abstract

SummaryDouble-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/ Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vb) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vb family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

“…Murine DN T cells were shown to prevent the onset of GvHD while mediating advantageous anti-leukemia effects. In addition, clinical studies pointed to a therapeutic benefit of human DN T cells, because the development and grade of GvHD were negatively correlated with the frequency of DN T cells after HSCT (4,5,9,10). However, our data revealed that IL-7 compromises the suppressive function of DN T cells.…”

“…Of interest, the first clinical studies on recipients of allogeneic stem cell grafts demonstrated an inverse correlation between the frequency of circulating DN T cells and the severity of acute GvHD (9,10). The observation that patients with circulating DN T cells frequencies .…”

Regulation of antigen‐expressing dendritic cells by double negative regulatory T cells

“…Consistent with these findings in mice, human DN Tregs have been shown to suppress autologous T cells in an Ag-specific fashion in vitro [4,7]. A recent study suggested that the frequency and total number of DN Tregs were significantly decreased in BM transplant patients who developed GVHD and that the CD8/DN Treg ratio directly correlated with severity of GVHD [17]. DN Tregs have also been implicated to play a role in anti-tumor immunity [18].…”

Immune Cell Infiltration in Malignant Middle Cerebral Artery Infarction: Comparison with Transient Cerebral Ischemia

“…À CD8 À T cells, which are involved in the downregulation of immune responses, 26 were similar to those of CD8 þ cells in both models. By contrast, CD4 þ cells were not significantly increased until 24 hours after pMCAO.…”