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

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

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 7

CSA attenuates acute GVHD but promotes alloantigen-specific CD4+ T cell survival.

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CSA attenuates acute GVHD but promotes alloantigen-specific CD4+ T cell ...
(A–D) Female B6D2F1 (I-Ed) recipients were transplanted with 5 × 106 PTPrca TCD BM, 5 × 104 luciferase-expressing TEaluc+ T cells and 6 × 105 Marilyn T cells, treated with saline or CSA (5 or 50 mg/kg/d) and taken for analysis on day 7. (A) Representative bioluminescence images and total flux of gut infiltrating TEaluc+ cells (n = 4–5 per group). (B) Representative flow cytometric plots and (C and D) frequencies, numbers and ratio of transferred T cells in spleens treated with lower dose CSA (5 mg/kg/d) (C: n = 8–10 per group from 2 experiments) or with higher dose CSA (50 mg/kg/d) (D: n = 5 per group). (E–H) Male B6 recipients were transplanted with 5 × 106 C57xPTP TCD BM, 5 × 104 TEa T cells and 6 × 105 luciferase-expressing Marilynluc+ T cells, treated with saline or CSA (5 or 50 mg/kg) and taken for analysis on day 7. (E) Representative bioluminescence images and total flux of gut infiltrating Marilynluc+ T cells (n = 4–5 per group). (F) Representative flow cytometric plots and (G and H) frequencies, numbers, and ratio of transferred T cells in spleens treated with lower dose CSA (5 mg/kg/d) (G: n = 8–10 per group from 2 experiments) or with higher dose CSA (50 mg/kg/d) (H: n = 5 per group). (I) B6D2F1 recipients were transplanted with B6 TCD BM (5 × 106) and 1 × 104 TEa T cells, treated with saline or higher dose CSA (50 mg/kg/d) and monitored for survival and clinical scores (n = 16 per group from 2 experiments). (J) Male B6 recipients were transplanted with 5 × 106 B6 TCD BM, 5 × 104 TEa T cells and 1 × 106 H-Y specific CD8+ T cells and treated with saline or CSA (50 mg/kg/d). Spleens were taken on day 7 (n = 12 per group from 2 experiments) and analyzed for the frequency, numbers, and ratio of transferred T cells. (A–H, and J) Data are presented as median ± interquartile range and analyzed with the Mann-Whitney U test; (I) Survival data are analyzed with log-rank test, and clinical scores are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.