Unexpected T-cell diversity in syngeneic graft-versus-host disease revealed by interaction with peptide-loaded soluble MHC class II molecules1

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

Blood ◽

10.1182/blood.v110.11.2164.2164 ◽

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*

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Murine T Lymphocytes Incapable of Producing Macrophage Inhibitory Protein-1 Are Impaired in Causing Graft-Versus-Host Disease Across a Class I But Not Class II Major Histocompatibility Complex Barrier

Blood ◽

10.1182/blood.v93.1.43 ◽

1999 ◽

Vol 93 (1) ◽

pp. 43-50 ◽

Cited By ~ 29

Author(s):

Jonathan S. Serody ◽

Donald N. Cook ◽

Suzanne L. Kirby ◽

Elizabeth Reap ◽

Thomas C. Shea ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Graft Versus Host Disease ◽

Class Ii ◽

Class I ◽

Wild Type ◽

Inhibitory Protein ◽

Host Disease ◽

Graft Versus Host

Abstract The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1−/− mice were administered to class I (B6.C-H2bm1) and class II disparate mice (B6-C-H2bm12). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1−/− mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1−/− splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4+ and CD8+ lymphocytes may need to be targeted.

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

Blood ◽

10.1182/blood-2003-01-0266 ◽

2003 ◽

Vol 102 (2) ◽

pp. 429-435 ◽

Cited By ~ 69

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.

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Murine T Lymphocytes Incapable of Producing Macrophage Inhibitory Protein-1 Are Impaired in Causing Graft-Versus-Host Disease Across a Class I But Not Class II Major Histocompatibility Complex Barrier

Blood ◽

10.1182/blood.v93.1.43.401k24_43_50 ◽

1999 ◽

Vol 93 (1) ◽

pp. 43-50 ◽

Cited By ~ 1

Author(s):

Jonathan S. Serody ◽

Donald N. Cook ◽

Suzanne L. Kirby ◽

Elizabeth Reap ◽

Thomas C. Shea ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Graft Versus Host Disease ◽

Class Ii ◽

Class I ◽

Wild Type ◽

Inhibitory Protein ◽

Host Disease ◽

Graft Versus Host

The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1−/− mice were administered to class I (B6.C-H2bm1) and class II disparate mice (B6-C-H2bm12). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1−/− mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1−/− splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4+ and CD8+ lymphocytes may need to be targeted.

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TNF-TNFR2 Interactions Are Critical for the Development of Intestinal Graft-Versus-Host Disease in MHC Class II-Disparate (C57BL/6J→C57BL/6J × bm12)F1Mice

The Journal of Immunology ◽

10.4049/jimmunol.168.6.3065 ◽

2002 ◽

Vol 168 (6) ◽

pp. 3065-3071 ◽

Cited By ~ 50

Author(s):

Geri R. Brown ◽

Ed Lee ◽

Dwain L. Thiele

Keyword(s):

Mhc Class Ii ◽

Graft Versus Host Disease ◽

Class Ii ◽

Host Disease ◽

Graft Versus Host

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MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota

Immunity ◽

10.1016/j.immuni.2019.08.011 ◽

2019 ◽

Vol 51 (5) ◽

pp. 885-898.e7 ◽

Cited By ~ 24

Author(s):

Motoko Koyama ◽

Pamela Mukhopadhyay ◽

Iona S. Schuster ◽

Andrea S. Henden ◽

Jan Hülsdünker ◽

...

Keyword(s):

Antigen Presentation ◽

Mhc Class Ii ◽

Graft Versus Host Disease ◽

Intestinal Epithelium ◽

Class Ii ◽

Host Disease ◽

Graft Versus Host ◽

Class Ii Antigen ◽

Mhc Class Ii Antigen

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CCR6 regulates CD4+ T-cell–mediated acute graft-versus-host disease responses

Blood ◽

10.1182/blood-2004-08-2996 ◽

2005 ◽

Vol 106 (1) ◽

pp. 18-26 ◽

Cited By ~ 61

Author(s):

Rosa Varona ◽

Vanesa Cadenas ◽

Lucio Gómez ◽

Carlos Martínez-A ◽

Gabriel Márquez

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Interleukin 10 ◽

Interferon Γ ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

We studied the role of chemokine receptor CCR6 in acute graft-versus-host disease (GvHD), a pathology in which activated, host antigen-specific donor T cells selectively damage tissues such as skin, liver, and gut. GvHD incidence was reduced in major histocompatibility complex (MHC) class II–mismatched recipients of CD4+ T cells from CCR6-deficient donors. In MHC-matched/minor histocompatibility antigen–mismatched recipients of CD4+CD45RBhigh T cells from CCR6-deficient donors, infiltration of CD45+ and CD4+ cells to skin and gut, as well as lesion onset, were significantly delayed, and pathologic symptoms were milder. Consistent with this, in skin and gut of recipients of naive T cells from CCR6-deficient donors we observed lower levels of interferon γ (IFN-γ), interleukin 10 (IL-10), and the chemokines that control activated T-cell homing. We suggest a role for CCR6 in recruiting alloreactive CD4+ T cells to target tissues and identify CCR6 as a potential therapeutic target for GvHD.

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