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Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity.


ABSTRACT: Acute graft-versus-host disease (aGVHD) is one major serious complication that is induced by alloreactive donor T cells recognizing host Ags and limits the success of allogeneic hematopoietic stem cell transplantation. In the current studies, we identified a critical role of Kras in regulating alloreactive T cell function during aGVHD. Kras deletion in donor T cells dramatically reduced aGVHD mortality and severity in an MHC-mismatched allogeneic hematopoietic stem cell transplantation mouse model but largely maintained the antitumor capacity. Kras-deficient CD4 and CD8 T cells exhibited impaired TCR-induced activation of the ERK pathway. Kras deficiency altered TCR-induced gene expression profiles, including the reduced expression of various inflammatory cytokines and chemokines. Moreover, Kras deficiency inhibited IL-6-mediated Th17 cell differentiation and impaired IL-6-induced ERK activation and gene expression in CD4 T cells. These findings support Kras as a novel and effective therapeutic target for aGVHD.

SUBMITTER: Luo L 

PROVIDER: S-EPMC7955895 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity.

Luo Lan L   Chen Yuhong Y   Chen Xiao X   Zheng Yongwei Y   Zhou Vivian V   Yu Mei M   Burns Robert R   Zhu Wen W   Fu Guoping G   Felix Juan C JC   Hartley Christopher C   Damnernsawad Alisa A   Zhang Jing J   Wen Renren R   Drobyski Williams R WR   Gao Chunji C   Wang Demin D  

Journal of immunology (Baltimore, Md. : 1950) 20201106 12


Acute graft-versus-host disease (aGVHD) is one major serious complication that is induced by alloreactive donor T cells recognizing host Ags and limits the success of allogeneic hematopoietic stem cell transplantation. In the current studies, we identified a critical role of Kras in regulating alloreactive T cell function during aGVHD. Kras deletion in donor T cells dramatically reduced aGVHD mortality and severity in an MHC-mismatched allogeneic hematopoietic stem cell transplantation mouse mod  ...[more]

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