Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease–associated autoimmunity

Abstract Abstract 1342 Poster Board I-364 Chronic graft versus host disease (GVHD) is an autoimmune-like disease, in which both donor CD4+ T and B cells play important roles in the pathogenesis. However, it is unclear how donor CD4+ T and B cells interact in the context of chronic GVHD. In our current studies, we found that, in a new chronic GVHD model of MHC-matched DBA/2 donor to BALB/c host, depletion of donor CD4+ T cells in transplants prevented donor B220+ B cell upregulation of co-stimulatory molecules (i.e. B7.1, B7.2, and MHC II), prevented donor B cell differentiation into syndecan+ IgG anti-dsDNA autoantibody-producing plasma cells, and prevented the induction of chronic GVHD. In addition, we found that donor CD4+ T cells were able to drive both marginal zone B (AA4.1−B220+CD1dhiCD23lo) and follicular B (AA4.1−B220+CD23hiCD1dlo) cells to become IgG autoantibody-producing cells. On the other hand, depletion of donor B220+ B cells in transplants prevented expansion of donor-type CD4+ T cells that proliferated in response to donor DC stimulation, prevented the skewing of TCR CDR3-length of the donor CD4+ T cells as revealed by TCR spectratyping, and prevented induction of chronic GVHD. These results indicate that donor CD4+ T and B cells mutually activate each other in the chronic GVHD recipients; alloreactive donor CD4+ T cells activate and drive donor B cell differentiation into IgG autoantibody producing cells, in turn, donor B cells mediate the expansion and TCR-spreading of autoreactive donor CD4+ T cells. Therefore, donor CD4+ T and B cells in transplants orchestrate the development of chronic GVHD. This work is supported by NIH R01 AI066008. Disclosures No relevant conflicts of interest to declare.

Download Full-text

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor

Frontiers in Immunology ◽

10.3389/fimmu.2021.761448 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hua Jiang ◽

Denggang Fu ◽

Alan Bidgoli ◽

Sophie Paczesny

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Graft Versus Host Disease ◽

Hematological Malignancies ◽

T Cell Differentiation ◽

T Cell Subsets ◽

General Description ◽

Host Disease ◽

Graft Versus Host

Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after HCT for malignant disease. Graft versus tumor (GVT) is a major component of the overall beneficial effects of allogeneic HCT in the treatment of hematological malignancies. Better understanding of GVHD pathogenesis is important to identify new therapeutic targets for GVHD prevention and therapy. Emerging data suggest opposing roles for different T cell subsets, e.g., IFN-γ producing CD4+ and CD8+ T cells (Th1 and Tc1), IL-4 producing T cells (Th2 and Tc2), IL-17 producing T cells (Th17 and Tc17), IL-9 producing T cells (Th9 and Tc9), IL-22 producing T cells (Th22), T follicular helper cells (Tfh), regulatory T-cells (Treg) and tissue resident memory T cells (Trm) in GVHD and GVT etiology. In this review, we first summarize the general description of the cytokine signals that promote the differentiation of T cell subsets and the roles of these T cell subsets in the pathogenesis of GVHD. Next, we extensively explore preclinical findings of T cell subsets in both GVHD/GVT animal models and humans. Finally, we address recent findings about the roles of T-cell subsets in clinical GVHD and current strategies to modulate T-cell differentiation for treating and preventing GVHD in patients. Further exploring and outlining the immune biology of T-cell differentiation in GVHD that will provide more therapeutic options for maintaining success of allo-HCT.

Download Full-text

Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease

Journal of Clinical Oncology ◽

10.1200/jco.2015.64.5929 ◽

2016 ◽

Vol 34 (10) ◽

pp. 1112-1121 ◽

Cited By ~ 302

Author(s):

Jennifer N. Brudno ◽

Robert P.T. Somerville ◽

Victoria Shi ◽

Jeremy J. Rose ◽

David C. Halverson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Graft Versus Host Disease ◽

B Cell Malignancies ◽

Host Disease ◽

Graft Versus Host ◽

Car T Cells ◽

Car T Cell ◽

Car T

Purpose Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. Methods We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient’s alloHSCT donor. Results Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease–negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. Conclusion Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.

Download Full-text

Faculty Opinions recommendation of Prevention of graft-versus-host disease by intra-bone marrow injection of donor T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1091039.544420 ◽

2007 ◽

Author(s):

Ignazio Majolino

Keyword(s):

Bone Marrow ◽

T Cells ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Donor T Cells

Download Full-text

Faculty Opinions recommendation of Cutting edge: Highly alloreactive dual TCR T cells play a dominant role in graft-versus-host disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1159729.621133 ◽

2009 ◽

Author(s):

Nick Gascoigne

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Dominant Role ◽

Cutting Edge ◽

Host Disease ◽

Graft Versus Host

Download Full-text

Faculty Opinions recommendation of Interleukin-2 and regulatory T cells in graft-versus-host disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13523956.15052056 ◽

2012 ◽

Author(s):

Mark Berneburg ◽

Lena Gonser

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Interleukin 2 ◽

Host Disease ◽

Graft Versus Host

Download Full-text

IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice

Nature Communications ◽

10.1038/s41467-021-21133-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Qingxiao Song ◽

Xiaoning Wang ◽

Xiwei Wu ◽

Tae Hyuk Kang ◽

Hanjun Qin ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Mononuclear Phagocyte ◽

Mononuclear Phagocytes ◽

Dependent Manner ◽

Steroid Resistant ◽

Host Disease ◽

Graft Versus Host ◽

Potential Efficacy ◽

Ifn Γ

AbstractEfforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17−IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.

Download Full-text

296 Near-infrared photoimmunotherapy targeting CD8 T cells inhibits cutaneous acute graft-versus-host disease

Journal of Investigative Dermatology ◽

10.1016/j.jid.2019.07.297 ◽

2019 ◽

Vol 139 (9) ◽

pp. S265

Author(s):

L. Freund ◽

G. Gräbe ◽

K. Schäkel

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Near Infrared ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Download Full-text

Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation

Blood ◽

10.1182/blood-2012-08-448977 ◽

2013 ◽

Vol 121 (18) ◽

pp. 3745-3758 ◽

Cited By ~ 136

Author(s):

Emily Blyth ◽

Leighton Clancy ◽

Renee Simms ◽

Chun K. K. Ma ◽

Jane Burgess ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Allogeneic Stem Cell Transplantation ◽

Organ Damage ◽

Host Disease ◽

Graft Versus Host ◽

Key Points

Key Points Infusion of CMV-specific T cells early posttransplant does not increase acute or chronic graft-versus-host disease. CMV-specific T cells early posttransplant reduce the need for pharmacotherapy without increased rates of CMV-related organ damage.

Download Full-text