Loss of jak2 protects cardiac allografts from chronic rejection by attenuating th1 response along with increased regulatory t cells

Hassan Mohammed Khair Ibrahim Higazi, Long He, Jing Fang, Fei Sun, Qing Zhou, Teng Huang, Xiaoyu He, Yi Wang, Fei Xiong, Ping Yang, Qilin Yu, Jinxiu Li, Kay Uwe Wagner, Bao Ling Adam, Shu Zhang, Cong Yi Wang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Chronic rejection acts as the most formidable obstacle for organ transplantation in clinical settings. Herein we demonstrated in a cardiac transplantation model that blockade of Janus kinase 2 (Jak2) provides protection for cardiac allografts against chronic rejection. Specifically, loss of Jak2 almost completely abolished the production of IFN-γ + Th1 cells, while the percentage of Foxp3 + regulatory T cells (Tregs) was significantly increased. As a result, loss of Jak2 significantly prolonged allograft survival (58 ± 30.6 days vs. 7 ± 0.3 days). Particularly, 4 out of 13 Jak2 deficient recipients (30%) showed long-term acceptance of allografts as manifested by the graft survival time > 100 days. Cellular studies revealed that Jak2 deficiency did not impact the intrinsic proliferative capability for CD4 + T cells in response to nonspecific polyclonal and allogenic stimulation. Mechanistic studies documented that the impaired Th1 development was caused by the attenuated IFN-γ/STAT1 and IL-12/STAT4 signaling along with repressed expression of Th1 transcription factors T-bet, Hlx and Runx3. However, the IL-2/STAT5 signaling remained intact, which ensured normal Treg development in Jak2 -/- naïve CD4 T cells. Together, our data support that blockade of Jak2 may have therapeutic potential for prevention and treatment of allograft rejection in clinical settings.

Original languageEnglish (US)
Article numberAJTR0088781
Pages (from-to)624-640
Number of pages17
JournalAmerican Journal of Translational Research
Volume11
Issue number2
StatePublished - 2019

Keywords

  • Allograft
  • Cardiac transplantation
  • Chronic rejection
  • Jak2
  • Regulatory T cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

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