ER stress sensor PERK promotes T cell pathogenicity in GVHD by regulating ER-associated degradation
Qiao Cheng, Hee-Jin Choi, Yongxia Wu, Xiaohong Yuan, Allison Pugel, Linlu Tian, Michael Hendrix, Denggang Fu, Reza Alimohammadi, Chen Liu, Xue-Zhong Yu
Qiao Cheng, Hee-Jin Choi, Yongxia Wu, Xiaohong Yuan, Allison Pugel, Linlu Tian, Michael Hendrix, Denggang Fu, Reza Alimohammadi, Chen Liu, Xue-Zhong Yu
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Research Article Immunology Inflammation

ER stress sensor PERK promotes T cell pathogenicity in GVHD by regulating ER-associated degradation

Abstract

Endoplasmic reticulum (ER) stress through IRE1/XBP1 is implicated in the onset and progression of graft-versus-host disease (GVHD), but the role of the ER stress sensor PERK in T cell allogeneic responses and GVHD remains unexplored. Here, we report that PERK is a key regulator in T cell allogeneic response and GVHD induction. PERK augments GVHD through increasing Th1 and Th17 population, while reducing Treg differentiation by activating the Nrf2 pathway. Genetic deletion or selective inhibition of PERK pharmacologically reduces GVHD while preserving graft-versus-leukemia (GVL) activity. At the cellular level, PERK positively regulates CD4+ T cell pathogenicity while negatively regulating CD8+ T cell pathogenicity in the induction of GVHD. At the molecular level, PERK interacts with SEL1L and regulates SEL1L expression, leading to augmented T cell allogeneic responses and GVHD development. In vivo, PERK deficiency in donor T cells alleviates GVHD through ER-associated degradation. Furthermore, pharmacological inhibition of PERK with AMG44 significantly suppresses the severity of GVHD induced by murine or human T cells. In summary, our findings validate PERK as a potential therapeutic target for the prevention of GVHD while preserving GVL responses, and uncover the mechanism by which PERK differentially regulates CD4+ versus CD8+ T cell allogeneic and antitumor responses.

Authors

Qiao Cheng, Hee-Jin Choi, Yongxia Wu, Xiaohong Yuan, Allison Pugel, Linlu Tian, Michael Hendrix, Denggang Fu, Reza Alimohammadi, Chen Liu, Xue-Zhong Yu

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Figure 4

PERK differentially regulates CD4+ and CD8+ T cell responses to alloantigens.

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PERK differentially regulates CD4+ and CD8+ T cell responses to alloanti...
(A and B) CD4+ T cells isolated from WT or PERK-cKO mice were stimulated with allogeneic APCs from BDF1 mice for 4 days; proliferation (CFSElo) of CD4+ T cells and levels of proinflammatory cytokines (TNF-α, IFN-γ) in CD4+ T cells were analyzed using flow cytometry (A). Percentages of CFSEloCD4+, CFSEloTNF-α+CD4+, and CFSEloIFN-γ+CD4+ T cells among gated H2Kd–CD4+ T cells are shown (B). (C and D) CD8+ T cells isolated from WT or PERK-cKO mice were stimulated with allogeneic APCs from BDF1 mice for 4 days; proliferation (CFSElo) of CD8+ T cells and levels of proinflammatory cytokines (TNF-α, IFN-γ) in CD8+ T cells were analyzed by flow cytometry (C). Percentages of CFSEloCD8+, CFSEloTNF-α+CD8+, and CFSEloIFN-γ+CD8+ T cells among gated H2Kd–CD8+ T cells are shown (D). (E–G) Lethally irradiated BALB/c recipients were injected with TCD-BM cells (5 × 106) alone or together with CD4+ T cells (1.25 × 106) from WT B6 or PERK-cKO donors. Survival (E), GVHD scores (F), and body weight (G) of BALB/c recipients were monitored through 80 days after BMT; n = 5 per BMT group. (H–J) Lethally irradiated BALB/c recipients (900 cGy) were injected with TCD-BM cells (5 × 106) alone or along with CD8+ T cells (2.5 × 106) from WT B6 or PERK-cKO donors and CD25-removed CD4+ T cells (0.5 × 106) from WT B6 mice. Survival (H), GVHD scores (I), and body weight (J) of BALB/c recipients were monitored through 80 days after BMT; n = 5 per BMT group. Log-rank (Mantel-Cox) test (E and H) and non-parametric Mann-Whitney U test (F, G, I, and J) were used to compare groups. Data in B and D are represented as mean ± SD with biological replicates; significance was determined using a 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.