Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells

Abstract

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHCexpressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigenpresenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation. IntroductionThe interaction of naive T cells and dendritic cells (DCs) is essential for initiating primary immune responses. DCs can be divided into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs) according to their immunophenotype and functional properties. 1-3 pDCs represent a CD11c int B220 ϩ DC subset that differs from the CD11c high B220 Ϫ major histocompatibility complex (MHC) class II high cDCs, commonly viewed as the classic stimulators of naive T cells. One distinctive feature of pDCs is their capacity to rapidly produce high levels of type I interferon (IFN) in response to viral and bacterial stimuli, highlighting the importance of pDCs in innate immune responses. 2-8 pDCs express low levels of surface MHC and classical costimulatory molecules; therefore, they are poor T-cell stimulators. [5][6][7][8][9][10][11] In contrast, pDCs matured with CD40 ligands or Toll-like receptor (TLR) ligands are potent antigen-presenting cells (APCs), capable of stimulating naive T-cell proliferation and differentiation to helper, killer, memory, and regulatory T cells in vitro. 7,12,13 In vivo, injection of pDCs activated by synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG), but not immature pDCs, is capable of eliciting antigen-specific CD8 ϩ T-cell responses. 10,14 On the other hand, OVA-pulsed pDCs protected mice against OVA-induced asthma development. 15 pDCs in the tumordraining lymph nodes express indole 2, 3-dioxygenase, and suppress antitumor T-cell responses. 16 In patients with ovarian cancer, large numbers of pDCs, which induced interleukin 10 (IL10)-producing regulatory T cells, were found in ascites. 17 pDCs mediate tolerance and prolong survival of cardiac allografts. 11,18,19 Several recent clinical observations...

Conventional dendritic cells are the critical donor APC presenting alloantigen after experimental bone marrow transplantation

“…Recipient cDCs 23 and pDCs 24 in isolation are able to induce allogeneic T-cell responses after transfer into MHC class II Ϫ/Ϫ recipients in vivo after conditioning. Although elegant, these studies demonstrate only that cDCs and pDCs in isolation can initiate GVHD, but their relative contribution to this process when all APC fractions are intact remains unclear.…”

Arsenic Trioxide Prevents Murine Sclerodermatous Graft-versus-Host Disease

“…Yet, the state of maturation of pDCs seems to be crucial in their ability to trigger GVHD. On the one hand, total-body irradiation induces inflammation and maturation of pDCs, which can subsequently activate T cells (6). On the other hand, Banovic et al (34) showed that precursors of pDCs, but not mature pDCs, can attenuate the symptoms of GVHD, emphasizing the differential functions of pDCs depending on the environment and the model of GVHD.…”

“…In contrast, the role of APCs in chronic GVHD was recently emphasized by the observation that costimulation of donor T cells through CD80 or CD86 on either host or donor APCs is necessary to induce chronic GVHD (32). pDCs are especially involved in the physiopathology of GVHD because the adoptive transfer of mature pDCs exacerbates GVHD, and they can stimulate donor T cells to trigger GVHD in the absence of other APCs (6,33). Yet, the state of maturation of pDCs seems to be crucial in their ability to trigger GVHD.…”

“…Moreover, among APCs, plasmacytoid DCs (pDCs) were shown to be pathogenic in GVHD. In the absence of other APCs, pDCs alone can stimulate donor T cells to trigger GVHD, and total-body irradiation is crucial for their maturation and the subsequent priming of alloreactive CD4 + T cells (6).…”

New perspectives on the biology of acute GVHD

“…31 However, host pDCs have been shown to induce GVHD in a TLR-independent manner. 32 In addition, GVHD prevents the maturation of donor pDCs. 33 Thus, the role of pDCs in acute GVHD is still controversial and confirmatory studies about their functions are necessary before a therapeutic approach based on this mechanism can be contemplated.…”