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Blood. 2016 Oct 20;128(16):2043-2054. doi: 10.1182/blood-2015-11-682468. Epub 2016 Jul 28.

T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire.

Author information

1
Bloodworks Northwest Research Institute, Seattle, WA.
2
Bayer Healthcare, South San Francisco, CA.
3
Benaroya Research Institute, Seattle, WA.
4
Uniformed Services University of the Health Sciences, Bethesda, MD.
5
Division of Hematology, Department Medicine, and.
6
Pediatric Hematology/Oncology, University of Washington, Seattle, WA; and.
7
Blood Disorders Program, Seattle Children's Hospital, Seattle, WA.

Abstract

Factor VIII (FVIII)-neutralizing antibodies ("inhibitors") are a serious problem in hemophilia A (HA). The aim of this study was to characterize HLA-restricted T-cell responses from a severe HA subject with a persistent inhibitor and from 2 previously studied mild HA inhibitor subjects. Major histocompatibility complex II tetramers corresponding to both of the severe HA subject's HLA-DRA-DRB1 alleles were loaded with peptides spanning FVIII-A2, C1, and C2 domains. Interestingly, only 1 epitope was identified, in peptide FVIII2194-2213, and it was identical to the HLA-DRA*01-DRB1*01:01-restricted epitope recognized by the mild HA subjects. Multiple T-cell clones and polyclonal lines having different avidities for the peptide-loaded tetramer were isolated from all subjects. Only high- and medium-avidity T cells proliferated and secreted cytokines when stimulated with FVIII2194-2213 T-cell receptor β (TCRB) gene sequencing of 15 T-cell clones from the severe HA subject revealed that all high-avidity clones expressed the same TCRB gene. High-throughput immunosequencing of high-, medium-, and low-avidity cells sorted from a severe HA polyclonal line revealed that 94% of the high-avidity cells expressed the same TCRB gene as the high-avidity clones. TCRB sequencing of clones and lines from the mild HA subjects also identified a limited TCRB gene repertoire. These results suggest a limited number of epitopes in FVIII drive inhibitor responses and that the T-cell repertoires of FVIII-responsive T cells can be quite narrow. The limited diversity of both epitopes and TCRB gene usage suggests that targeting of specific epitopes and/or T-cell clones may be a promising approach to achieve tolerance to FVIII.

PMID:
27471234
PMCID:
PMC5073183
DOI:
10.1182/blood-2015-11-682468
[Indexed for MEDLINE]
Free PMC Article

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