Extrafollicular CD4+ T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease

Ruishu Deng, Christian Hurtz, Qingxiao Song, Chanyu Yue, Gang Xiao, Hua Yu, Xiwei Wu, Markus Muschen, Stephen Forman, Paul J. Martin and Defu Zeng ()
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Ruishu Deng: Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope
Christian Hurtz: University of California
Qingxiao Song: Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope
Chanyu Yue: The Beckman Research Institute of City of Hope
Gang Xiao: University of California
Hua Yu: The Beckman Research Institute of City of Hope
Xiwei Wu: The Beckman Research Institute of City of Hope
Markus Muschen: University of California
Stephen Forman: Hematologic Malignancies and Stem Cell Transplantation Institute, The Beckman Research Institute of City of Hope
Paul J. Martin: Fred Hutchinson Cancer Research Center, University of Washington
Defu Zeng: Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome mediated by pathogenic CD4+ T and B cells, but the function of extrafollicular and germinal center CD4+ T and B interactions in cGVHD pathogenesis remains largely unknown. Here we show that extrafollicular CD4+ T and B interactions are sufficient for inducing cGVHD, while germinal center formation is dispensable. The pathogenesis of cGVHD is associated with the expansion of extrafollicular CD44hiCD62loPSGL-1loCD4+ (PSGL-1loCD4+) T cells. These cells express high levels of ICOS, and the blockade of ICOS/ICOSL interaction prevents their expansion and ameliorates cGVHD. Expansion of PSGL-1loCD4+ T cells is also prevented by BCL6 or Stat3 deficiency in donor CD4+ T cells, with the induction of cGVHD ameliorated by BCL6 deficiency and completely suppressed by Stat3 deficiency in donor CD4+ T cells. These results support that Stat3- and BCL6-dependent extrafollicular CD4+ T and B interactions play critical functions in the pathogenesis of cGVHD.

Date: 2017
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DOI: 10.1038/s41467-017-00880-2

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