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Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD
Yewei Wang, … , Ping Zhang, Geoffrey R. Hill
Yewei Wang, … , Ping Zhang, Geoffrey R. Hill
Published June 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e170125. https://doi.org/10.1172/JCI170125.
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Research Article Immunology Article has an altmetric score of 25

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

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Abstract

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.

Authors

Yewei Wang, Md Ashik Ullah, Olivia G. Waltner, Shruti S. Bhise, Kathleen S. Ensbey, Christine R. Schmidt, Samuel R.W. Legg, Tomoko Sekiguchi, Ethan L. Nelson, Rachel D. Kuns, Nicole S. Nemychenkov, Erden Atilla, Albert C. Yeh, Shuichiro Takahashi, Julie R. Boiko, Antiopi Varelias, Bruce R. Blazar, Motoko Koyama, Simone A. Minnie, Andrew D. Clouston, Scott N. Furlan, Ping Zhang, Geoffrey R. Hill

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Figure 5

CSA expands alloreactive CD4+ TCM with high self-renewal capacity.

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CSA expands alloreactive CD4+ TCM with high self-renewal capacity.
(A–H)...
(A–H) B6D2F1 recipients were transplanted with B6 BM (5 × 106) + T cells (2 × 106) and treated with saline or CSA (5 or 50 mg/kg/d). Spleens were taken on day 7 and analyzed with high-parameter flow cytometry (concatenated from 4–5 samples per group). (A–C) Donor CD4+ T cells were analyzed for: (A) t-SNE plots colored by FlowSOM populations, (B) Heatmap of marker expression (MFI) across FlowSOM populations, and (C) t-SNE plots (colored by FlowSOM populations) across groups. (D–F) Donor CD8+ T cells were analyzed for: (D) t-SNE plots colored by FlowSOM populations, (E) Heatmap of marker expression (MFI) across FlowSOM populations, and (F) t-SNE plots (colored by FlowSOM populations) across groups. (G and H) Expression of TCF-7/TCF-1 and Ly108 in TN (CD44–CD62L+), TEM (CD44+CD62L–), and TCM (CD44+CD62L+) subsets of donor T cells in untreated mice (n = 9 per group from 2 experiments). (I) B6D2F1 recipients were transplanted as above. Spleens were taken on day 17 and analyzed for the memory phenotypes of donor CD4+ and CD8+ T cells (n = 9–10 per group from 2 experiments). (J) B6D2F1 recipients were transplanted with B6 TCD BM (5 × 106) + TEa TCR transgenic T cells (5 × 103) and treated with saline or CSA (50 mg/kg/d). Spleens were taken on day 17 and TEa cells were analyzed (n = 6 per group from 1 experiment). Data are presented as median ± interquartile range and analyzed with 1-way ANOVA (H) or Mann-Whitney U test (I and J). **P < 0.01; ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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