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JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction.

Publication ,  Journal Article
Khatri, A; Todd, JL; Kelly, FL; Nagler, A; Ji, Z; Jain, V; Gregory, SG; Weinhold, KJ; Palmer, SM
Published in: JCI Insight
March 22, 2023

Chronic lung allograft dysfunction (CLAD) is the leading cause of death in lung transplant recipients. CLAD is characterized clinically by a persistent decline in pulmonary function and histologically by the development of airway-centered fibrosis known as bronchiolitis obliterans. There are no approved therapies to treat CLAD, and the mechanisms underlying its development remain poorly understood. We performed single-cell RNA-Seq and spatial transcriptomic analysis of explanted tissues from human lung recipients with CLAD, and we performed independent validation studies to identify an important role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in airway epithelial cells that contributes to airway-specific alloimmune injury. Specifically, we established that activation of JAK-STAT signaling leads to upregulation of major histocompatibility complex 1 (MHC-I) in airway basal cells, an important airway epithelial progenitor population, which leads to cytotoxic T cell-mediated basal cell death. This study provides mechanistic insight into the cell-to-cell interactions driving airway-centric alloimmune injury in CLAD, suggesting a potentially novel therapeutic strategy for CLAD prevention or treatment.

Duke Scholars

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 22, 2023

Volume

8

Issue

6

Location

United States

Related Subject Headings

  • T-Lymphocytes, Cytotoxic
  • Lung Transplantation
  • Lung
  • Humans
  • Cell Death
  • Allografts
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

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Khatri, A., Todd, J. L., Kelly, F. L., Nagler, A., Ji, Z., Jain, V., … Palmer, S. M. (2023). JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction. JCI Insight, 8(6). https://doi.org/10.1172/jci.insight.167082
Khatri, Aaditya, Jamie L. Todd, Fran L. Kelly, Andrew Nagler, Zhicheng Ji, Vaibhav Jain, Simon G. Gregory, Kent J. Weinhold, and Scott M. Palmer. “JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction.JCI Insight 8, no. 6 (March 22, 2023). https://doi.org/10.1172/jci.insight.167082.
Khatri A, Todd JL, Kelly FL, Nagler A, Ji Z, Jain V, et al. JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction. JCI Insight. 2023 Mar 22;8(6).
Khatri, Aaditya, et al. “JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction.JCI Insight, vol. 8, no. 6, Mar. 2023. Pubmed, doi:10.1172/jci.insight.167082.
Khatri A, Todd JL, Kelly FL, Nagler A, Ji Z, Jain V, Gregory SG, Weinhold KJ, Palmer SM. JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction. JCI Insight. 2023 Mar 22;8(6).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 22, 2023

Volume

8

Issue

6

Location

United States

Related Subject Headings

  • T-Lymphocytes, Cytotoxic
  • Lung Transplantation
  • Lung
  • Humans
  • Cell Death
  • Allografts
  • 42 Health sciences
  • 32 Biomedical and clinical sciences