Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

Abstract

IntroductionAllogeneic bone marrow transplantation (BMT) is the definitive curative therapy for the majority of hematologic malignancies and severe immunodeficiencies. The major complication of allogeneic BMT remains graft-versus-host disease (GVHD) in which the skin, gastrointestinal tract, and liver are preferentially damaged by the transplanted donor immune system. The therapeutic potential of BMT relates to the graft-versus-leukemia (GVL) effect, which eradicates host malignancy after BMT and is mediated by donor T and natural killer cells. 1 GVHD occurs in the majority (50%-70%) of recipients and is largely responsible for the high rate of mortality associated with allogeneic BMT. There is thus a pressing need for new treatment approaches to both prevent and treat GVHD, ideally without inhibiting GVL.The complex interactions resulting in the generation of T-cellmediated alloimmune responses depend on antigen presentation, cognate interactions between donor T cells and antigen-presenting cells (APCs), and the concomitant production of soluble and membrane-bound costimulatory molecules by APCs and T cells (reviewed in Morris et al 2 ). The initiation of GVHD absolutely depends on the presence of mature donor T cells in the graft. 2 Thus, although TLR signaling undoubtedly contributes to the activation of APCs early after transplantation, 3 it is likely that donor T cells provide the most critical signal. In this regard, the CD40-CD40L pathway appears to be of major importance, as demonstrated by the induction of tolerance following disruption of this receptor-ligand interaction. 4 The subsequent molecular mechanisms controlling APC function in tolerance and immunity are poorly defined. The NF-kB/Rel family of proteins include 5 subunits: c-Rel, RelA, RelB, NF-kB1, and NF-kB2, which form homodimers or heterodimers. At steady state, most of these proteins are inactive within the cytoplasm, bound by inhibitory IkB proteins. Activation by the classical pathway within a broad range of cells (including APCs and T cells) occurs as a result of a variety of membrane signals, including TNF, IL-1, and Toll receptors, that allow nuclear import of c-Rel and RelA heterodimers with subsequent transcriptional activation of inflammatory proteins. Activation by the alternative pathway within APCs is the result of lymphocyte interactions and signaling through the lymphotoxin-␤ receptor, BAFF receptor or CD40, resulting in nuclear import of p52/RelB heterodimers and transcriptional activation of characterized and uncharacterized proteins that result in maturation and antigenpresenting activity within professional APCs. [5][6][7] Because APCs are known to be critical for the initiation and maintenance of GVHD 8,9 and their activation occurs rapidly after transplantation, 10 we hypothesized that maintaining host APCs in a state of RelB inactivity during conditioning would promote the induction of peripheral tolerance after allogeneic stem cell transplantation (SCT). We found that the lack of RelB within either host or donor APCs l...

Immunotherapy with Costimulatory Dendritic Cells To Control Autoimmune Inflammation

“…1E), further demonstrating their reduced costimulatory capacity. Because these data are consistent with previous analyses of DCs from RelB 2/2 radiation chimeras, which have no inflammatory disease, this reduction in specific cytokine secretion by DCs is RelB intrinsic and not due to DC "exhaustion" in the face of chronic autoimmune inflammation (34). In response to LPS, RelB 2/2 and RelB +/2 DCs produced similar levels of TNF.…”

“…Consistent with their central tolerance and DC defects, RelB 2/2 mice develop spontaneous Th2 T cell-dependent multisystem autoimmune, myeloproliferative, and allergic disease from birth, characterized by failure to thrive; splenomegaly (lymph nodes are absent); inflammatory disease of skin, eyes, lungs, liver, and pancreas; high levels of serum IgE; and death by ∼3 mo of age (29,30). T celldeficient RelB 2/2 mice do not develop inflammatory disease, indicating a defect in the control of effector T cell or Treg functions in these mice either directly or as result of the lack of interaction with mature DCs with high RelB activity (32)(33)(34). We show in this article that T EMs in this model are efficiently regulated by Foxp3 + Tregs when costimulated by RelB-sufficient DCs but not DCs deficient in RelB or CD80/CD86.…”

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

“…10,11 To ensure rigorous and persistent depletion of cDCs throughout the period in which Tg T cells were present, 100 ng/dose DT was administered to recipients of CD11c.DTR Tg BM grafts on day 8, 10, and 12 posttransplant to maintain depletion For personal use only. on May 10, 2018. by guest www.bloodjournal.org From throughout the period of TEa T-cell response in vivo.…”

Soluble lymphotoxin is an important effector molecule in GVHD and GVL

“…T-cell depletion of BM was performed by incubating the cells with hybridoma supernatants containing CD4 (RL172.4), CD8 (TIB211), and anti-Thy1.2 (HO-13-4) monoclonal antibodies, followed by incubation with rabbit complement (Cedarlane Laboratories), as previously described. 16 Resulting cell suspensions contained less than 1% contamination of viable CD3 ϩ T cells. Donor T cells (H-2 b ) for use in in vitro functional assays were sorted based on CD4 or CD8 staining by fluorescence-activated cell sorting (FACS), using a MoFlo instrument (DakoCytomation) to more than 95% purity.…”