An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD

Jonathan C. Poe, Wei Jia, Hsuan Su, Sarah Anand, Jeremy J. Rose, Prasanthi V. Tata, Amy N. Suthers, Corbin D. Jones, Pei Fen Kuan, Benjamin G. Vincent, Jonathan S. Serody, Mitchell E. Horwitz, Vincent T. Ho, Steven Z. Pavletic, Frances T. Hakim, Kouros Owzar, Dadong Zhang, Bruce R. Blazar, Christian W. Siebel, Nelson J. ChaoIvan Maillard, Stefanie Sarantopoulos

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this “NOTCH2-BCR axis” in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.

Original languageEnglish (US)
Pages (from-to)2131-2145
Number of pages15
JournalBlood
Volume130
Issue number19
DOIs
StatePublished - Nov 9 2017

Bibliographical note

Funding Information:
This work was supported by grants from the Leukemia & Lymphoma Society (6497-16 [S.S.], 6462-15 [B.R.B. and I.M.]); by the US Department of Defense (W81XWH-11-1-0537 [S.S.]); and by the National Institutes of Health: R01 HL 129061-01 (National Heart, Lung, and Blood Institute [S.S.]), R01 AI 091627 (National Institute of Allergy and Infectious Diseases [I.M.]), and P01C142106 and R01AI34495 (National Cancer Institute and National Institute of Allergy and Infectious Diseases [B.R.B.]).

Publisher Copyright:
© 2017, American Society of Hematology. All rights reserved.

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