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Nat Commun. 2017 Oct 17;8(1):978. doi: 10.1038/s41467-017-00880-2.

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

Deng R1,2,3, Hurtz C4,5, Song Q1,2,6, Yue C7, Xiao G4,8, Yu H7, Wu X9, Muschen M4,8, Forman S2, Martin PJ10, Zeng D11,12.

Author information

1
Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
2
Hematologic Malignancies and Stem Cell Transplantation Institute, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
3
Sanford Burnham Prebys Medical, Discovery Institute, La Jolla, CA, 92307, USA.
4
Department of Laboratory Medicine, University of California, San Francisco, CA, 94143, USA.
5
Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
6
Department of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, 350000, China.
7
Department of Cancer Immunotherapeutic and Tumor Immunology, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
8
Department of Systems Biology, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
9
Department of Molecular and Cellular Biology, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
10
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, 98109, USA.
11
Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA. dzeng@coh.org.
12
Hematologic Malignancies and Stem Cell Transplantation Institute, The Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA. dzeng@coh.org.

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.Chronic graft-versus-host disease (cGVHD) is mediated by specific CD4 and B cells, but the relative contribution of extrafollicular and germinal centre (GC) T-B interaction is unclear. Here the authors show that the extrafollicular expansion of a specific CD4 T subset is sufficient for inducing cGVHD while GC is dispensable.

PMID:
29042531
PMCID:
PMC5645449
DOI:
10.1038/s41467-017-00880-2
[Indexed for MEDLINE]
Free PMC Article

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