miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation

Abstract

Because miR-181a has been described to alter T cell activation, we hypothesized that manipulation of miR-181a expression in donor T cells may alter acute graft-versus-host disease (aGvHD) after allogeneic bone marrow transplantation (BMT). We therefore analyzed the impact of enhanced and reduced miR-181a expression in donor T cells on aGvHD induction by lentiviral gene transfer into primary T cells and using miR-181a/b-1 2/2 T cells, respectively. BMT-recipient mice receiving donor T cells with enhanced miR-181a expression showed no signs of aGvHD and survived for the time of follow-up, whereas T cells lacking miR-181a/b-1 accelerated aGvHD. In line with these data, analysis of donor T cells in blood, secondary lymphoid organs, and target organs of aGvHD after BMT showed significantly reduced numbers of miR-181a-transduced T cells, as compared with controls. In addition, expansion of activated T cells with enhanced miR-181a expression was reduced in vitro and in vivo. We further show that anti-apoptotic BCL-2 protein expression is reduced in murine and human T cells upon overexpression of miR-181a, suggesting that regulation of BCL-2-expression by miR-181a may contribute to altered alloreactivity of T cells in aGvHD. These data indicate that proteins regulated by miR-181a may be therapeutic targets for aGvHD prevention. The Journal of Immunology, 2016, 196: 3927-3934.A llogeneic stem cell or bone marrow (BM) transplantation (BMT) is the most effective and often unique curative therapy for a variety of high-risk hematological malignancies, BM failure syndromes, and congenital immune deficiencies. However, graft-versus-host disease (GvHD) remains the most frequent severe complication in BMT, contributing largely to nonrelapse mortality. Acute GvHD (aGvHD) is initiated by an aggressive immune response of donor-derived alloreactive T cells directed against host tissues. After allopriming, donor T cells migrate to typical GvHD target organs such as skin, liver, and/or gut, inducing a strong immune response, which ultimately leads to organ damage and/or failure (1). Accordingly, aGvHD prevention and treatment are performed with immunosuppressive drugs such as corticosteroids, calcineurin inhibitors, and different Abs, among others. However, steroid refractory intestinal aGvHD still has a mortality rate of close to 100%. Therefore, new therapeutic strategies are urgently needed.MicroRNAs (miRNA) are small noncoding RNAs involved in posttranscriptional regulation of gene expression (2, 3). Despite many efforts, however, the precise physiological function of individual miRNAs and their pathophysiological contribution to different disease states still remain elusive. In aGvHD, a role for miRNAs in allogeneic donor T cells has recently been described. Overexpression of miR-155 in donor T cells leads to increased GvHD mortality, whereas miR-155 deficiency prevents aGvHD (4). Furthermore, increased miR-146a expression in donor T cells prevents from GvHD development by targeting TNFR-associated factor 6, leading to reduced T...

Expression of Serum microRNAs is Altered During Acute Graft-versus-Host Disease

“…In this context, it may be surprising that miR-374 levels are lower at aGvHD diagnosis; however, nTregs comprise just 5–10% of the circulating CD4 + population, and pro-inflammatory cytokines released during the acute response can suppress nTreg function (41). miR-181 acts as an intrinsic modulator of T-cell sensitivity and selection (26), and in accordance with the present results showing lower miR-181 expression at aGvHD diagnosis, BMT-recipient mice transplanted with miR-181 negative donor T-cells demonstrate accelerated aGvHD (42). …”

MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

“…In peripheral T cells, levels of miR-181a are even further reduced when compared to their intrathymic counterparts and expression is even further reduced in Treg cells [40]. Both CD4 and CD8 T cells loose expression of miR-181a upon activation in vitro, consistent with lower expression of miR-181a in memory vs. naive T cells [41,42]. Moreover, miR-181a is dynamically expressed in T cells over the lifetime of an organism, with its levels progressively decreasing with increasing age [43,44].…”

MicroRNA in T-Cell Development and T-Cell Mediated Acute Graft-Versus-Host Disease

“…miR-181a acts as a rheostat for T cell sensitivity to antigen by downregulation of several phosphatases downstream of the TCR ( 76 ). Primary T cells overexpressing miR-181a failed to induce experimental GvHD, whereas, conversely, donor T cells lacking miR-181a/b-1 accelerated acute GvHD in the same model ( 92 ). Overexpression of miR-181a resulted in decreased T cell survival, most likely because of reduced expression of anti-apoptotic BCL-2 protein expression.…”