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Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity. J Immunol 2020 12 15;205(12):3480-3490

Date

11/08/2020

Pubmed ID

33158956

Pubmed Central ID

PMC7955895

DOI

10.4049/jimmunol.2000006

Scopus ID

2-s2.0-85097490484   1 Citation

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.

Author List

Luo L, Chen Y, Chen X, Zheng Y, Zhou V, Yu M, Burns R, Zhu W, Fu G, Felix JC, Hartley C, Damnernsawad A, Zhang J, Wen R, Drobyski WR, Gao C, Wang D

Authors

Xiao Chen MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Juan Felix MD Vice Chair, Director, Professor in the Pathology department at Medical College of Wisconsin
Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Allografts
Animals
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Graft vs Host Disease
Graft vs Leukemia Effect
Hematopoietic Stem Cell Transplantation
Interleukin-6
MAP Kinase Signaling System
Mice
Mice, Transgenic
Proto-Oncogene Proteins p21(ras)
Th17 Cells