Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-06, Vol.134 (11), p.1-17
Main Authors: Wang, Yewei, Ullah, Md Ashik, Waltner, Olivia G, Bhise, Shruti S, Ensbey, Kathleen S, Schmidt, Christine R, Legg, Samuel Rw, Sekiguchi, Tomoko, Nelson, Ethan L, Kuns, Rachel D, Nemychenkov, Nicole S, Atilla, Erden, Yeh, Albert C, Takahashi, Shuichiro, Boiko, Julie R, Varelias, Antiopi, Blazar, Bruce R, Koyama, Motoko, Minnie, Simone A, Clouston, Andrew D, Furlan, Scott N, Zhang, Ping, Hill, Geoffrey R
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Calcineurin
Calcineurin inhibitors
Calcineurin Inhibitors - pharmacology
CD4 antigen
CD4-Positive T-Lymphocytes - immunology
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell activation
Cell self-renewal
Chronic Disease
Cloning
Cyclophosphamide
Cyclosporine - pharmacology
Cytokines
Disease prevention
Drug dosages
Drug therapy
Drug withdrawal
Female
Gene expression
Graft versus host disease
Graft versus host reaction
Graft vs Host Disease - immunology
Graft vs Host Disease - pathology
Graft vs Host Disease - prevention & control
Health aspects
Identification and classification
Immunological memory
Immunological tolerance
Immunosuppressive agents
Isoantigens - immunology
Lymphocytes
Lymphocytes T
Memory cells
Memory T Cells - immunology
Mice
Pathogenesis
Physiological aspects
Prevention
Prophylaxis
Risk factors
Stem cell transplantation
Stem cells
T cell receptors
T cells
T-Lymphocyte Subsets - immunology
Tacrolimus
Tacrolimus - pharmacology
Testing
Transplantation
Transplants & implants
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Summary:Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.
ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI170125