T cell receptor excision circle levels in CD94-expressing CD8 T Cells during graft-versus-host disease

Abstract Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8+ T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8+ T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8+ T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8+ T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.

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PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells

Blood ◽

10.1182/blood-2010-04-283119 ◽

2011 ◽

Vol 117 (3) ◽

pp. 1030-1041 ◽

Cited By ~ 54

Author(s):

Wolfgang Koestner ◽

Martin Hapke ◽

Jessica Herbst ◽

Christoph Klein ◽

Karl Welte ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Adoptive Transfer ◽

Cell Receptor ◽

Graft Versus Host ◽

Graft Versus Leukemia

Abstract Adoptive transfer (AT) of T cells forced to express tumor-reactive T-cell receptor (TCR) genes is an attractive strategy to direct autologous T-cell immunity against tumor-associated antigens. However, clinical effectiveness has been hampered by limited in vivo persistence. We investigated whether the use of major histocompatibility complex–mismatched T cells would prolong the in vivo persistence of tumor-reactive TCR gene expressing T cells by continuous antigen-driven proliferation via the endogenous potentially alloreactive receptor. Donor-derived CD8+ T cells engineered to express a TCR against a leukemia-associated antigen mediated strong graft-versus-leukemia (GVL) effects with reduced graft-versus-host disease (GVHD) severity when given early after transplantation. AT later after transplantation resulted in a complete loss of GVL. Loss of function was associated with reduced expansion of TCR-transduced T cells as assessed by CDR3 spectratyping analysis and PD-1 up-regulation on T cells in leukemia-bearing recipients. PD-L1 blockade in allogeneic transplant recipients largely restored the GVL efficacy without triggering GVHD, whereas no significant antileukemia effects of PD-L1 blockade were observed in syngeneic controls. These data suggest a clinical approach in which the AT of gene-modified allogeneic T cells early after transplantation can provide a potent GVL effect without GVHD, whereas later AT is effective only with concurrent PD-L1 blockade.

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T-Cell Receptor Vα Usage by Effector CD4+Vβ11+ T Cells Mediating Graft-versus-Host Disease Directed to Minor Histocompatibility Antigens

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2006.11.012 ◽

2007 ◽

Vol 13 (3) ◽

pp. 265-276 ◽

Cited By ~ 5

Author(s):

Christine G. DiRienzo ◽

George F. Murphy ◽

Thea M. Friedman ◽

Robert Korngold

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Graft Versus Host Disease ◽

Cell Receptor ◽

Histocompatibility Antigens ◽

Host Disease ◽

Minor Histocompatibility Antigens ◽

Graft Versus Host

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Of Mice, Not Men: No Evidence for Graft-versus-Host Disease in Humans Receiving T-Cell Receptor–Transduced Autologous T Cells

Molecular Therapy ◽

10.1038/mt.2010.195 ◽

2010 ◽

Vol 18 (10) ◽

pp. 1744-1745 ◽

Cited By ~ 50

Author(s):

Steven A Rosenberg

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Graft Versus Host Disease ◽

Cell Receptor ◽

Host Disease ◽

Graft Versus Host

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Cytomegalovirus-Specific CD8+ T-Cells With Different T-Cell Receptor Affinities Segregate T-Cell Phenotypes and Correlate With Chronic Graft-Versus-Host Disease in Patients Post-Hematopoietic Stem Cell Transplantation

Frontiers in Immunology ◽

10.3389/fimmu.2018.00760 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 4

Author(s):

Thomas Poiret ◽

Rebecca Axelsson-Robertson ◽

Mats Remberger ◽

Xiao-Hua Luo ◽

Martin Rao ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

T Cell Phenotypes ◽

Cell Phenotypes

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Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood ◽

10.1182/blood.2020004871 ◽

2020 ◽

Author(s):

Cheng Yin Yuan ◽

Vivian Zhou ◽

Garrett Sauber ◽

Todd M Stollenwerk ◽

Richard Komorowski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Acute Gvhd ◽

Cannabinoid Receptor ◽

Therapeutic Targeting ◽

Host Disease ◽

Graft Versus Host

Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

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Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease

Blood Advances ◽

10.1182/bloodadvances.2018027474 ◽

2019 ◽

Vol 3 (7) ◽

pp. 984-994 ◽

Cited By ~ 6

Author(s):

Jennifer S. Whangbo ◽

Haesook T. Kim ◽

Sarah Nikiforow ◽

John Koreth ◽

Ana C. Alho ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Low Dose ◽

B Cell Lymphoma ◽

Host Disease ◽

Graft Versus Host ◽

Response Groups

Abstract Patients with chronic graft-versus-host disease (cGVHD) have a paucity of regulatory CD4 T cells (CD4Tregs) that mediate peripheral tolerance. In clinical trials, daily low-dose interleukin-2 (IL-2) has been administered safely for prolonged periods in patients with steroid-refractory cGVHD. Peripheral CD4Tregs expand dramatically in all patients during IL-2 therapy but clinical improvement was observed in ∼50% of patients. Here, we examined the impact of low-dose IL-2 therapy on functional T-cell markers and the T-cell repertoire within CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8+ T cells. IL-2 had profound effects on CD4Tregs homeostasis in both response groups including selective expansion of the naive subset, improved thymic output, and increased expression of Ki67, FOXP3, and B-cell lymphoma 2 within CD4Tregs. Similar changes were not seen in CD4Tcons or CD8 T cells. Functionally, low-dose IL-2 enhanced, in vitro, CD4Treg-suppressive activity in both response groups, and all patient CD4Tcons were similarly suppressed by healthy donor CD4Tregs. High-throughput sequencing of the T-cell receptor β (TCRβ) locus demonstrated that low-dose IL-2 therapy increased TCR repertoire diversity and decreased evenness within CD4Tregs without affecting CD4Tcons or CD8 T cells. Using clone-tracking analysis, we observed rapid turnover of highly prevalent clones in CD4Tregs as well as the conversion of CD4Tcons to CD4Tregs. After 12 weeks of daily IL-2, clinical responders had a greater influx of novel clones within the CD4Treg compartment compared with nonresponders. Further studies to define the function and specificity of these novel CD4Treg clones may help establish the mechanisms whereby low-dose IL-2 therapy promotes immune tolerance.

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Molecular analysis of T-cell receptor repertoire in bone marrow transplant recipients: evidence for oligoclonal T-cell expansion in graft-versus-host disease lesions

Blood ◽

10.1182/blood.v87.7.3032.bloodjournal8773032 ◽

1996 ◽

Vol 87 (7) ◽

pp. 3032-3044 ◽

Cited By ~ 38

Author(s):

X Liu ◽

V Chesnokova ◽

SJ Forman ◽

DJ Diamond

Keyword(s):

Bone Marrow ◽

T Cell ◽

T Cell Receptor ◽

Graft Versus Host Disease ◽

Cell Receptor ◽

Supporting Evidence ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Beta 2

We have analyzed the T-cell receptor (TCR) V beta repertoire using polymerase chain reaction (PCR) in a cohort of eight patients receiving allogeneic bone marrow transplantation (BMT) from related and unrelated donors at the City of Hope. Results of PCR studies from graft-versus- host disease (GVHD) skin lesions show a bias in the usage of TCR V beta families, whereas examination of peripheral blood (PB) withdrawn at the same time did not reveal a similar phenomenon. In one such family, TCR V beta 2 is predominantly expressed in 7 of 7 biopsy specimens examined. V beta 2 TCR expression from these patients was analyzed more extensively using a combination of individual TCR gene cloning, followed by sequence analysis. We found evidence of oligoclonal expansion of single V beta 2-bearing TCRs in GVHD lesions, and in the PB of some patients after diagnosis of GVHD. In contrast, GVHD-negative biopsy samples showed no evidence for clonotypic TCR amplification. Sequence-specific TCR CDR3 region probes were derived from analysis of the predominant expressed TCR in GVHD lesions, and used to probe Southern blots of amplified V beta 2 TCR mRNA from PB and tissue from BMT recipients and their respective donors. In most cases the probes are highly specific in detecting TCR expression from GVHD lesions alone, although in several instances expression could be detected in PB after GVHD diagnosis. These data provide supporting evidence for the hypothesis that acute GVHD is associated with expansion of T-cell clones expressing antigen-specific TCRs that may contribute to the disease pathology.

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