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The ADAMTS13 1239–1253 peptide is a dominant HLA-DR1-restricted CD4 + T-cell epitope

Laurent Gilardin 1 Sandrine Delignat 1 Ivan Peyron 1 Mathieu Ing 1 Yu-Chun Lone 2 Bagirath Gangadharan 3 Baptiste Michard 4 Yousra Kherabi Meenu Sharma 1 Anastas Pashov 5 Jean-Baptiste Latouche 6, 7 Mohamad Hamieh Olivier Toutirais 8 Pascale Loiseau 9 Lionel Galicier 10 Agnes Veyradier 11 Srini Kaveri 1 Bernard Maillere 12 Paul Coppo 13 Sébastien Lacroix-Desmazes 3
1 CRC - Centre de Recherche des Cordeliers
2 Greffes d'Epitheliums et Regulation de l'Activation Lymphocytaire
3 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
4 HUS - Les Hôptaux universitaires de Strasbourg
5 Institut Stephan Angeloff
6 GMFC - Génétique du cancer et des maladies neuropsychiatriques
7 PANTHER - Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices
8 Hôpital Côte de Nacre [CHU Caen]
9 Immunogénétique humaine
10 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
11 Service d'Hématologie Biologique [Béclère]
12 UMR_S567 / UMR 8104 - Institut Cochin
13 U1170 Inserm - Hématopoïèse normale et pathologique
Abstract : Acquired thrombotic thrombocytopenic purpura is a rare and severe disease characterized by auto-antibodies directed against “A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13th member" (ADAMTS13), a plasma protein involved in hemostasis. Involvement of CD4+ T cells in the pathogenesis of the disease is suggested by the IgG isotype of the antibodies. However, the nature of the CD4+ T-cell epitopes remains poorly characterized. Here, we determined the HLA-DR-restricted CD4+ T-cell epitopes of ADAMTS13. Candidate T-cell epitopes were predicted in silico and binding affinities were confirmed in competitive enzyme-linked immunosorbent assays. ADAMTS13-reactive CD4+ T-cell hybridomas were generated following immunization of HLA-DR1 transgenic mice (Sure-L1 strain) and used to screen the candidate epitopes. We identified the ADAMTS131239–1253 peptide as the single immunodominant HLA-DR1-restricted CD4+ T-cell epitope. This peptide is located in the CUB2 domain of ADAMTS13. It was processed by dendritic cells, stimulated CD4+ T cells from Sure-L1 mice and was recognized by CD4+ T cells from an HLA-DR1-positive patient with acute thrombotic thrombocytopenic purpura. Interestingly, the ADAMTS131239–1253 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4+ T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS131239–1253-loaded HLA-DR tetramers.
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Journal articles
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02379896
Contributor : Jean-Baptiste Latouche <>
Submitted on : Monday, November 25, 2019 - 10:33:22 PM
Last modification on : Monday, December 14, 2020 - 9:46:48 AM

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COMUE-NORMANDIE | RIIP | RIIP_SA | FNCLCC | UPMC | UNIV-PARIS5 | UNIROUEN | U1234PANTHER | SORBONNE-UNIVERSITE | UNIV-PARIS7 | CORDELIERS | EPHE | USPC | CNRS | SU-SCIENCES | IGR | UNIV-PARIS | UP-SANTE | PSL | SU-TI

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Laurent Gilardin, Sandrine Delignat, Ivan Peyron, Mathieu Ing, Yu-Chun Lone, et al.. The ADAMTS13 1239–1253 peptide is a dominant HLA-DR1-restricted CD4 + T-cell epitope. Haematologica, Ferrata Storti Foundation, 2017, 102 (11), pp.1833-1841. ⟨10.3324/haematol.2015.136671⟩. ⟨hal-02379896⟩

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