Host Plasmacytoid or Conventional Dendritic Cells Alone Are Sufficient To Initiate Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2164-2164
Author(s):  
Motoko Koyama ◽  
Daigo Hashimoto ◽  
Kazutoshi Aoyama ◽  
Ken-ichi Matsuoka ◽  
Kennosuke Karube ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Class Ii ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Alloantigen expression on host dendritic cells (DCs) is critical to initiate GVHD. DCs can be divided into two main subpopulations; conventional DCs (cDCs) and plasmacytoid DCs (pDCs), however, the contribution of each DC subset to elicit GVHD remains unclear. We examined the ability of cDCs and pDCs to initiate GVHD. pDCs, cDCs and B cells were isolated from C57BL/6 (B6: H–2b) mice treated with Flt3 ligand in order to expand DCs. pDCs were enriched from bone marrow by depleting CD3+, CD19+, CD11b+, and CD49b+ cells, followed by a FACS sorting of CD11cint B220+ cells. cDCs and B cells were sorted from splenocytes as CD11chi B220− cells and CD11c− B220+ cells, respectively. Isolated pDCs showed plasmacytoid morphology, produced IFN-α in response to CpG oligonucleotide. Although pDCs stimulated allogeneic T cells far less potently than cDCs, stimulation with CpG enhanced their allostimulatory capacity as potent as cDCs. We compared the ability of each DC subset to initiate GVHD by an add-back study of MHC class II-expressing DCs into MHC class II-deficient (II−/−) mice that were resistant to CD4-dependent GVHD. Lethally irradiated II−/− B6 mice were injected with 2 × 106 pDCs, cDCs or B cells from wild-type (II+/+) B6 mice on day -1 and injected with 2 × 106 CD4+ T cell from BALB/c (H–2d) mice on day 0. A flow cytometric analysis of the mesenteric lymph nodes on day +5 demonstrated significantly greater expansion of donor CD4+ T cells in recipients of pDCs or cDCs than those of B cells (Table). While injection of B cells did not cause any sign of GVHD, injection of pDCs or cDCs alone was sufficient to produce clinical and pathological GVHD (Table), thus breaking GVHD resistance of II−/− mice. We next examined the ability of pDCs to induce CD8-dependent GVHD in MHC-matched transplant using mice deficient in functional MHC class I expression (β2m−/−). Again, injection of pDCs or cDCs alone was sufficient to cause expansion of donor CD8+ T cells (p<0.05). We next asked whether signaling through Toll-like receptors (TLRs) could be required for pDCs to initiate GVHD. However, injection of pDCs isolated from MyD88/TRIF-double deficient mice was able to initiate GVHD as potent as wild-type pDCs, thus demonstrating that pDCs initiate GVHD in a TLR signaling independent manner. These results provide important information for developing strategies aimed at inactivating host DCs to prevent GVHD. Impact of each APC subpopulation on GVHD APC Donor CD4 expansion (×103±SE) Clinical GVHD score (mean±SE) Pathological GVHD score (mean±SE) *p<0.05 compared with B cells B cell 0.1 ± 0.0 2.1 ± 0.2 2.1 ± 0.2 pDC 5.3 ± 2.4* 4.3 ± 0.3* 7.4 ± 0.5* cDC 9.7 ± 3.8 * 3.8 ± 0.5 * 7.2 ± 0.7*

Resting B Cells Suppress CD8+ T Cell Function and Prevent the Induction of Graft Versus Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3111-3111
Author(s):  
David S. Ritchie ◽  
Victoria Watt
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
In Vivo Models ◽  
Host Disease ◽  
Graft Versus Host

Abstract B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells, induce T cell anergy via TGF-b production, down regulate IL-12 production by dendritic cells (DC) and influence Th1/Th2 differentiation via the production of regulatory cytokines. Through these mechanisms, B cells can exert a regulatory function in in vivo models of T cell immunity including, experimental autoimmune encephalitis (EAE) and rheumatoid arthritis (RA). Recently, B cells have been shown to be essential in the prevention of effector T cell differentiation in a model of autoimmunity. We have previously shown that resting B cells inhibited tumor protection induced by dendritic cells vaccination. Inhibition of DC immunity by B cells was independent of presentation of major histocompatibility molecule (MHC) class-I bound tumor antigen but dependent on the expression of class-II MHC. Furthermore the inhibitory effect of B cells was lost if the B cells were activated by CD40L or if CD4+/CD25+ regulatory T cells (Treg) were depleted. These studies have been further extended to examine the role of resting B cells on the induction and severity of graft versus host disease (GVHD) induced in a major MHC mismatch model. We have found that mice transplanted with B cell depleted marrow revealed more rapid CD8+ T cell engraftment, higher IL-2 and IFN-γ production, more severe GVHD and shorter survival. Conversely, those who received additional resting B cells at the time of marrow infusion were substantially protected from GVHD. These findings indicate that resting B cells may regulate T cell activation, in part via the suppressive effects of Treg, but also through their important role in T cell homeostasis. Resting B cells may therefore limit the efficacy of DC based immunotherapy or alternatively be used therapeutically to limit CD8+ T cell autoimmunity including GVHD.

scholarly journals In vivo dynamics of T cells and their interactions with dendritic cells in mouse cutaneous graft-versus-host disease

2019 ◽  
Vol 3 (14) ◽  
pp. 2082-2092
Author(s):  
Sarah Morin-Zorman ◽  
Christian Wysocki ◽  
Jieqing Zhu ◽  
Hongmei Li ◽  
Sylvain Zorman ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Cd4 Cells ◽  
Tcr Signaling ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloSCT). By static microscopy, cutaneous GVHD lesions contain a mix of T cells and myeloid cells. We used 2-photon intravital microscopy to investigate the dynamics of CD4+ and CD8+ T cells and donor dendritic cells (DCs) in cutaneous GVHD lesions in an MHC-matched, multiple minor histocompatibility antigen-mismatched (miHA) model. The majority of CD4 and CD8 cells were stationary, and few cells entered and stopped or were stopped and left the imaged volumes. CD8 cells made TCR:MHCI-dependent interactions with CD11c+ cells, as measured by the durations that CD8 cells contacted MHCI+ vs MHCI− DCs. The acute deletion of Langerin+CD103+ DCs, which were relatively rare, did not affect CD8 cell motility and DC contact times, indicating that Langerin−CD103− DCs provide stop signals to CD8 cells. CD4 cells, in contrast, had similar contact durations with MHCII+ and MHCII− DCs. However, CD4 motility rapidly increased after the infusion of an MHCII-blocking antibody, indicating that TCR signaling actively suppressed CD4 movements. Many CD4 cells still were stationary after anti-MHCII antibody infusion, suggesting CD4 cell heterogeneity within the lesion. These data support a model of local GVHD maintenance within target tissues.

Impaired thymic negative selection causes autoimmune graft-versus-host disease

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 429-435 ◽  
Author(s):  
Takanori Teshima ◽  
Pavan Reddy ◽  
Chen Liu ◽  
Debra Williams ◽  
Kenneth R. Cooke ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Negative Selection ◽  
Class Ii ◽  
Systemic Autoimmune Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Autoreactive T Cell

AbstractAnimal models with impaired thymic negative selection do not always cause autoimmune diseases despite the development of an autoreactive T-cell repertoire. We investigated the requirements for the de velopment of systemic autoimmune disease by using bone marrow chimeras that lacked expression of major histocompatibility complex (MHC) class II on thymic antigen-presenting cells (APCs), leading to impaired negative selection. We found that impaired negative selection mediated by absence of MHC class II, but not MHC class I, permitted the development of systemic autoimmune disease that is indistinguishable from acute graft-versus-host disease (GVHD). Thymectomy prevented disease, confirming the causal association of the thymus with its development. Adoptive transfer of CD4+ T cells caused GVHD in secondary hosts only when they were irradiated, and cotransfer of peripheral CD4+ and CD8+ T cells from naive mice prevented the disease. These results demonstrate that impaired thymic negative selection can cause lethal autoimmune disease indistinguishable from acute GVHD in the context of a proinflammatory milieu when peripheral regulatory mechanisms are absent.

scholarly journals 2050 Identifying the role and immunobiological mechanisms of Fli-1 mediated pathogenicity in graft Versus host disease

2018 ◽  
Vol 2 (S1) ◽  
pp. 14-15
Author(s):  
Steven Schutt ◽  
Yongxia Wu ◽  
Anusara Daenthanasanmak ◽  
David Bastian ◽  
Carole Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Plasma Cells ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Knock Out ◽  
Graft Versus Host ◽  
Knock Out Mice

OBJECTIVES/SPECIFIC AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative procedure for hematological malignancies. Chronic graft Versus host disease (cGVHD) is a lethal complication that often develops after allo-HCT. Fli-1 is an aberrantly expressed protein in cancers including erythroleukemia and melanoma, while being implicated in pathogenesis of systemic lupus in mice and humans, a disease with marked similarity to cGVHD. METHODS/STUDY POPULATION: cGVHD was induced using hematopoietic cells from conditional knock-out mice deficient for the fli-1 gene specifically on T cells and progression of cGVHD in murine allo-HCT recipients was monitored using a clinical scoring system, and changes in activation status of hematopoietic cell populations were quantified using flow cytometry. RESULTS/ANTICIPATED RESULTS: Recipients transplanted with fli-1 deficient T cells exhibited reduced cGVHD clinical scores compared with littermate wild-type controls. Donor-grafts containing fli-1 deficient T cells were associated with restrained T-cell responses including reduced Interferon-y cytokine production, PD-1 expression, and differentiation into follicular helper T cells. fli-1 T-cell deficient donor-grafts also improved donor B-cell reconstitution and reduced plasma cells in allo-HCT recipients relative to littermate wild-type control donor-graft recipients. DISCUSSION/SIGNIFICANCE OF IMPACT: Thus, inhibiting Fli-1 represents a promising therapeutic strategy for the goal of preventing cGVHD after allo-HCT while also directly targeting cancers which aberrantly express Fli-1.

Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4780-4789 ◽  
Author(s):  
Kaori Sato ◽  
Kawori Eizumi ◽  
Tomohiro Fukaya ◽  
Shigeharu Fujita ◽  
Yumiko Sato ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
T Cell Response ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Naturally Occurring ◽  
Regulatory Dendritic Cells

Abstract Chronic graft-versus-host disease (cGVHD) is a limiting factor in allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of leukemia and other malignancies. Relative to the process that initiates and promotes cGVHD, the regulation is poorly understood. In this study, we examined the role of naturally occurring regulatory dendritic cells (DCregs) in murine major histocompatibility complex (MHC)-compatible and multiple minor histocompatibility antigen (miHAg)–incompatible model of cGVHD in alloHSCT. DCregs generated from bone marrow in vitro (BM-DCregs) exclusively expressed CD200 receptor 3 (CD200R3), which exerted a suppressive function in the Ag-specific CD4+ T-cell response. CD49+CD200R3+ cells showed similarities in phenotype and function to BM-DCregs, which formally distinguishes them from other leukocytes, suggesting that they are the natural counterpart of BM-DCregs. Treatment of the recipient mice after alloHSCT with the recipient-type CD49+CD200R3+ cells as well as BM-DCregs protected against cGVHD, and the protection was associated with the generation of Ag-specific anergic CD4+ T cells as well as CD4+CD25+Foxp3+ regulatory T cells (Tregs) from donor-derived alloreactive CD4+CD25−Foxp3− T cells. In addition, the depletion of CD49+CD200R3+ cells before alloHSCT enhanced the progression of cGVHD. In conclusion, CD49+CD200R3+ cells act as naturally occurring DCregs to regulate the pathogenesis of cGVHD in alloHSCT mediated through the control of the transplanted alloreactive CD4+ T cells.

scholarly journals Graft-Versus-Host Disease Impairs the Histone Methyltransferase Dot1l-Regulated Reconstitution of Plasmacytoid Dendritic Cells in Mice Undergoing Allo-HSCT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 477-477
Author(s):  
Yuanyuan Tian ◽  
Lijun Meng ◽  
Hongshuang Yu ◽  
Elizabeth O. Hexner ◽  
Leizhen Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Histone Methyltransferase ◽  
Plasmacytoid Dendritic Cells ◽  
Hematopoietic Stem ◽  
Steady State Condition ◽  
Host Disease ◽  
Graft Versus Host

Abstract Plasmacytoid dendritic cells (pDCs) derived either from adoptive transfer from the donor graft or stem cell reconstitution can attenuate and prevent graft-versus-host disease (GVHD) in both pre-clinical and clinical settings. However, the reconstitution of donor pDCs is severely impaired during GVHD via an unknown mechanism. Here we demonstrate that the histone methyltransferase Dot1l, which specifically catalyzes methylation of histone H3 at lysine 79 (H3K79me), is critical for regulating the commitment and differentiation of pDCs from hematopoietic stem cells (HSCs) and we observed its function was severely impaired in GVHD mice. We have previously demonstrated that Flt3L-induced DCs can program allogeneic T cells to reduce their GVHD toxicity (Blood 2016). Using this platform, we explored candidate histone methyltransferase(s) that affected pDC development. We found the inhibitor specific to Dot1l dramatically decreased the frequency and number of pDCs in cultures compared to other chemical probes that inhibit Ezh2, MLL1, G9a and Jmjd3, respectively. Under steady-state condition, pDCs develop from HSCs through successive steps of lineage commitment and differentiation: multiple potent progenitors (MPP) → macrophage and DC progenitors (MDP) → common DC progenitors (CDP). Upon culturing in the presence of Flt3L+SCF, MPP produced 2-fold and 5-fold more pDCs than MDP and HSCs, respectively, over 6 days' incubation. For this reason, we focused on evaluating the effect of Dot1l deletion on pDC development from MPP and CDP, which represent the early and later stage of pDC progenitors, respectively. To examine the specific role of Dot1l in DC development, we crossed Dot1l conditional knock mice (Dot1lf/f) to ER-Cre B6 mice to generate ER-Cre.Dot1lf/f B6 mice. We administered tamoxifen to ER-Cre.Dot1lf/f B6 mice at day 0 and day +1 to delete Dot1l, highly purified MPP and CDP, and cultured them in the presence of Flt3L+SCF. Deletion of Dot1l led to significant decrease of (3- to 5-fold) pDCs from MPP but marginally decreased CDP production of pDCs. These results suggest that Dot1l is required for the initial commitment and differentiation of MPP into pDCs or the expansion of selected pDCs. To test it, we added Dot1l inhibitor SGC to the cultures containing wild-type (WT) mouse-derived MPP, CDP and pDCs. Inhibiting Dot1l with SGC decreased both the frequency (3-fold) and number (5-fold) of pDCs in the MPP culture compared to control, however, it did not affect the generation of pDCs from the cultures of either CDP or pDCs. Thus, Dot1l regulates the commitment and differentiation of pDCs during the MPP stage. To understand the molecular mechanism by which Dot1l regulates pDC commitment and differentiation, we examined the expression of transcription factor Tcf4, which promotes pDC development, and Id2, which antagonizes Tcf4 effects on pDCs. Dot1l inhibition led to 2-fold reduction of Tcf4 expression and 5-fold increase of Id2 in Flt3L-induced bone marrow cells. ChIP assays confirmed the presence of high amount of Dot1l-catalyzed H3K79me2 at the promoter regions of Id2 and Tcf4 loci. Retroviral introduction of Tcf4 into hematopoietic progenitors lacking Dot1l restored their capacity to produce pDCs in cultures. These findings clearly establish that Tcf4 is the down-stream effector of Dot1l to control pDC development. Building on these observations, we finally examined whether GVHD may impair the reconstitution of donor pDCs through a mechanism of reducing Dot1l expression and function. Using the C57BL/6 (B6) into Balb/c mouse GVHD model, we confirmed the loss of donor pDCs in GVHD recipients at day 14 and day 21 after transplantation and, observed that these GVHD mice had 3- to 12-fold fewer MPP and CDP compared to normal donor mice. Additionally, both HSCs and MPP derived from GVHD mice showed significant reduction of H3K79me2 compared to their normal counterparts. Finally, adoptive transfer of donor BM-derived pDCs attenuated the incidence and severity of GVHD in Balb/c mice receiving B6 T cells. Collectively, these data suggest that GVHD-mediated inflammation profoundly decreases Dot1l function in engrafted donor DC progenitors, leading to damaged reconstitution of donor pDCs. Novel strategies that target Dot1l and its-regulated transcriptional programs may improve the reconstitution of donor pDCs to inhibit GVHD while also promoting anti-leukemia activity in recipients undergoing allo-HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Blood ◽  
2019 ◽  
Vol 134 (23) ◽  
pp. 2092-2106 ◽  
Author(s):  
Andrew N. Wilkinson ◽  
Karshing Chang ◽  
Rachel D. Kuns ◽  
Andrea S. Henden ◽  
Simone A. Minnie ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Donor T Cells ◽  
Principal Source

Key Points DCs are the principal source of IL-6 dysregulation after alloSCT. IL-6–dependent GVHD is driven by classical signaling of IL-6R on donor T cells but is regulated by trans signaling.

scholarly journals Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1756-1764 ◽  
Author(s):  
Yukimi Sakoda ◽  
Daigo Hashimoto ◽  
Shoji Asakura ◽  
Kengo Takeuchi ◽  
Mine Harada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell–depleted bone marrow cells from major histocompatibility complex [MHC] class II–deficient (H2-Ab1−/−) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

Integrative Analysis of Long Noncoding RNAs in Patients with Graft-versus-Host Disease

2020 ◽  
Vol 143 (6) ◽  
pp. 533-551 ◽  
Author(s):  
Feiyan Wang ◽  
Lan Luo ◽  
Zhenyang Gu ◽  
Nan Yang ◽  
Li Wang ◽  
...  
Keyword(s):  
B Cells ◽  
Signaling Pathway ◽  
Microarray Analysis ◽  
Graft Versus Host Disease ◽  
Differentially Expressed ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Qrt Pcr ◽  
Bcr Signaling

<b><i>Background:</i></b> Chronic graft-versus-host disease (cGVHD) remains a major cause of late non-recurrence mortality despite remarkable improvements in the field of allogeneic hematopoietic stem cell transplantation. Although recent studies have found that B-cell receptor (BCR)-activated B cells contribute to pathogenesis in cGVHD, the specific molecular mechanisms of B cells in this process remain unclear. <b><i>Methods:</i></b> In our study, human long noncoding RNA (lncRNA) microarrays and bioinformatic analysis were performed to identify different expressions of lncRNAs in peripheral blood B cells from cGVHD patients compared with healthy ones. The differential expression of lncRNA was confirmed in additional samples by quantitative real-time polymerase chain reaction (qRT-PCR). <b><i>Results:</i></b> The microarray analysis revealed that 106 of 198 differentially expressed lncRNAs were upregulated and 92 were downregulated in cGVHD patients compared with healthy controls. Intergenic lncRNAs accounted for the majority of differentially expressed lncRNAs. A KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that the differentially expressed mRNAs, which were coexpressed with lncRNA, between the cGVHD group and the healthy group were significantly enriched in the BCR signaling pathway. Further analysis of the BCR signaling pathway and its coexpression network identified three lncRNAs with the strongest correlation with BCR signaling and cGVHD, as well as a series of protein-coding genes and transcription factors associated with them. The three candidate lncRNAs were further validated in another group of cGVHD patients by qRT-PCR. <b><i>Conclusions:</i></b> This is the first study on the correlation between lncRNA and cGVHD using lncRNA microarray analysis. Our study provides novel enlightenment in exploring the molecular pathogenesis of cGVHD.

Host γd T cells Exacerbate Experimental Acute Graft-Versus-Host Disease through Activation of Host Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3045-3045
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Chen Liu ◽  
D. Keith Bishop ◽  
James L.M. Ferrara
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Serum Levels ◽  
Host Disease ◽  
Graft Versus Host ◽  
Full Intensity

Abstract Large numbers of T cells bearing γd T cell receptors are present in graft-versus-host disease (GVHD) target tissues. We investigated the potential role of host γd T cells during acute GVHD in a well-characterized GVHD model following full intensity conditioning (11 Gy TBI). BM and spleen T cells from BALB/c (H2d) donors were transplanted into wild type (wt) B6, aß T cell deficient B6 (aß −/−) or γd T cell deficient B6 (γd −/−) hosts. γd −/− hosts demonstrated significantly better day 35 survival (85%) than wt (40%) or aß−/− hosts (18%) (P&lt;0.05). Reconstitution of γd −/− B6 hosts with B6 type γd T cells 24 hr prior to BMT restored lethal GVHD (50 % day 35 survival). In vivo, γd −/− B6 hosts demonstrated at least a five fold reduction in donor T cell expansion and cytokine production. In vitro, T cells proliferated less when co-cultured with allogeneic γd −/− dendritic cells (DCs) than with wt DCs (40,127 ± 1634 vs. 72,503 ± 1296, P&lt;0.05). BM-derived DCs cultured with γd T cells caused greater proliferation of allogeneic T cells than DCs cultured with aß T cells (15.1 ± 21 x 104 vs. 5.1 ± 1.2 x 104, P&lt;0.05). We next tested the effect of γd T cells on host DCs in vivo using a model system in which only the DCs injected prior to BMT expressed the alloantigen that stimulated the GVHD reaction. MHC Class II −/− B6 mice that had been depleted of γd T cells were given 11 Gy TBI and injected one day prior to BMT with B6 DCs that had been co-cultured either with γd T cells or with medium. On day 0 both groups of recipient mice were injected with BM plus splenic T cells from allogeneic bm12 donors. On day +5, CD4+ donor T cells expanded four times more in recipients of DCs co-cultured with γd T cells than in recipients of control DCs and serum levels of TNF-a were significantly higher (36.7 + 6.8 vs. 21.3 + 3.7 pg/ml, P&lt;0.05). Together these data demonstrate that γd T cells amplify the stimulatory function of host DCs and increase the severity of GVHD, suggesting that a new therapeutic target for the prevention of the major BMT toxicity.

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