title: Circulating T follicular helper cells with increased function during chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (cGVHD) remains a major late complication of allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have established that both donor B and T cells contribute to immune pathology in cGVHD but the mechanisms responsible for coordinated B- and T-cell responses directed against recipient antigens have not been understood. T follicular helper cells (TFH) play an important role in the regulation of B-cell immunity. We performed extensive phenotypic and functional analysis of circulating TFH (cTFH) and B cells in 66 patients after HSCT. Patients with active cGVHD had a significantly lower frequency of cTFH compared with patients without cGVHD. This was associated with higher CXCL13 plasma levels suggesting increased homing of TFH to secondary lymphoid organs. In patients with active cGVHD, cTFH phenotype was skewed toward a highly activated profile with predominance of T helper 2 (Th2)/Th17 subsets. Activated cTFH in patients with cGVHD demonstrated increased functional ability to promote B-cell immunoglobulin secretion and maturation. Moreover, the activation signature of cTFH was highly correlated with increased B-cell activation and plasmablast maturation in patients after transplant. These studies provide new insights into the immune pathogenesis of human cGVHD and identify TFH as a key coordinating element supporting B-cell involvement in this disease.
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; UMR CNRS 5164, Bordeaux University, Bordeaux, France;
authors.forename: Edouard
authors.initials: E
authors.lastname: Forcade
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Harvard School of Public Health, Boston, MA;
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Kathy
authors.initials: K
authors.lastname: Wang
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Ana C
authors.initials: AC
authors.lastname: Alho
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.affiliation: Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D064591:Allografts; D002478:Cells, Cultured; D002908:Chronic Disease; D018920:Coculture Techniques; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D038041:Lymphopoiesis; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D059467:Transcriptome; D055815:Young Adult