Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis
Olivia Thomas, Urszula Rykaczewska, Marina Galesic, Rianne T.M. van der Burgt, Nils Hallén, Filippo Ferro, Mattias Bronge, Zoe Marti, Yue Li, Alexandra Hill Rique, Jianing Lin, Aleksa Krstic, Alicja Gromadzka, Andras Levente Szonder, Chiara Sorini, Maria Reina-Campos, Ting Sun, Leslie A. Rubio Rodríguez-Kirby, Özge Dumral, Rasmus Berglund, Majid Pahlevan Kakhki, Milena Z. Adzemovic, Manuel Zeitelhofer, Birce Akpinar, Katarina Tengvall, Ola B. Nilsson, Erik Holmgren, Chiara Starvaggi Cucuzza, Klara Asplund Högelin, Guro Gafvelin, Katharina Fink, Gonçalo Castelo‐Branco, Maria Needhamsen, Mohsen Khademi, Fredrik Piehl, Torbjörn Gräslund, Lars Alfredsson, Harald Lund, Per Uhlén, Ingrid Kockum, R Martin, M Jagodic, Hans Grönlund, Guerreiro-Cacais AO, Tomas Olsson
Abstract
Epstein-Barr virus (EBV) infection constitutes a prerequisite for multiple sclerosis (MS) development, and cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies was previously demonstrated in persons with MS (pwMS). Here, we show that ANO2-specific CD4 + T cells are more frequent in pwMS. Immunization of SJL/J mice with ANO2 or EBNA1 led to cross-reactive CD4 + T cell and antibody responses. ANO2 pre-immunization led to exacerbated experimental autoimmune encephalomyelitis (EAE), an effect mediated by CD4 + T cells, as confirmed by adoptive transfer experiments. T cell clones with cross-reactivity to EBNA1 and ANO2 could be isolated from natalizumab-treated pwMS, and sequencing of EBNA1- and ANO2-specific T cell receptors (TCRs) revealed a significant repertoire overlap. We thus report the first mechanistic evidence that EBNA1 CD4 + T cells can target the MS autoantigen ANO2, thereby establishing a link between EBV infection and neuroinflammation.