Faculty Collaboration Database

Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice. Blood Adv 2019 Oct 22;3(20):3099-3110

Date

10/28/2019

Pubmed ID

31648333

Pubmed Central ID

PMC6849959

DOI

10.1182/bloodadvances.2019000650

Scopus ID

2-s2.0-85074935557 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

The development of neutralizing anti-FVIII antibodies (inhibitors) is a major complication of FVIII protein replacement therapy in patients with hemophilia A (HA). Although multiple lines of evidence indicate that the immune response against FVIII is CD4 T-cell-dependent and many FVIII-derived CD4 epitopes have already been discovered, the role of T follicular helper (TFH) cells in FVIII inhibitor development is unknown. TFH cells, a newly identified subset of CD4 T cells, are characterized by expression of the B-cell follicle-homing receptor CXCR5 and PD-1. In this study, we show for the first time that IV FVIII immunization induces activation and accumulation and/or expansion of PD-1+CXCR5+ TFH cells in the spleen of FVIII-deficient (FVIIInull) mice. FVIII inhibitor-producing mice showed increased germinal center (GC) formation and increased GC TFH cells in response to FVIII immunization. Emergence of TFH cells correlated with titers of anti-FVIII inhibitors. Rechallenge with FVIII antigen elicited recall responses of TFH cells. In vitro FVIII restimulation resulted in antigen-specific proliferation of splenic CD4+ T cells from FVIII-primed FVIIInull mice, and the proliferating cells expressed the TFH hallmark transcription factor BCL6. CXCR5+/+ TFH-cell-specific deletion impaired anti-FVIII inhibitor production, confirming the essential role of CXCR5+/+ TFH cells for the generation of FVIII-neutralizing antibodies. Together, our results demonstrate that the induction of activated TFH cells in FVIIInull mice is critical for FVIII inhibitor development, suggesting that inhibition of FVIII-specific TFH-cell activation may be a promising strategy for preventing anti-FVIII inhibitor formation in patients with HA.

Author List

Jing W, Chen J, Cai Y, Chen Y, Schroeder JA, Johnson BD, Cui W, Shi Q

Authors

Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

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

Animals
Antibodies, Neutralizing
CD4-Positive T-Lymphocytes
Disease Models, Animal
Factor VIII
Germinal Center
Hemophilia A
Immunization
Immunophenotyping
Lymphocyte Activation
Lymphocyte Depletion
Mice
Mice, Knockout
Programmed Cell Death 1 Receptor
Receptors, CXCR5
T-Lymphocytes, Helper-Inducer