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

Laurent Gilardin (1, 2) , Sandrine Delignat (1) , Ivan Peyron (1) , Mathieu Ing (1) , Yu-Chun Lone (3) , Bagirath Gangadharan (1) , Baptiste Michard (4, 1) , Yousra Kherabi (1) , Meenu Sharma (1) , Anastas Pashov (1, 5) , Jean-Baptiste Latouche (6, 7) , Mohamad Hamieh (7) , Olivier Toutirais (8) , Pascale Loiseau (9, 10) , Lionel Galicier (10) , Agnes Veyradier (11) , Srini Kaveri (1) , Bernard Maillere (12, 13) , Paul Coppo (2, 14) , Sébastien Lacroix-Desmazes (1)

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 CNR-MAT - Centre national de référence des microangiopathies thrombotiques
3 INSERM - Institut National de la Santé et de la Recherche Médicale
4 HUS - Les Hôpitaux Universitaires de Strasbourg
5 BAS - Bulgaria Academy of Sciences = Académie des Sciences de Bulgarie
6 PANTHER - Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices
7 Hôpital Charles Nicolle [Rouen]
8 Hôpital Côte de Nacre [CHU Caen]
9 Immunogénétique humaine
10 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
11 Hôpital Lariboisière-Fernand-Widal [APHP]
12 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
13 MTS - Médicaments et Technologies pour la Santé
14 CHU Saint-Antoine [AP-HP]

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 ADAMTS13$^{1239–1253}$ 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 ADAMTS13$^{1239–1253}$3 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4$^+$ T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS13$^{1239–1253}$-loaded HLA-DR tetramers.

Domaines: Sciences du Vivant [q-bio]

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, 2017, 102 (11), pp.1833-1841. ⟨10.3324/haematol.2015.136671⟩. ⟨hal-02379896⟩