Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6

Abstract

// Karin M. E. Andersson 1, * , Mikael Brisslert 1, * , Nicola Filluelo Cavallini 1 , Mattias N. D. Svensson 1, 4 , Amanda Welin 1 , Malin C. Erlandsson 1 , Michael J. Ciesielski 2 , Gergely Katona 3 , Maria I. Bokarewa 1 1 Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 2 Department of Neurosurgery, Roswell Park Cancer Institute and State University of New York School of Medicine and Biomedical Sciences, Buffalo, NY, USA 3 Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden 4 Division of Cellular Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA * These authors have contributed equally to this work Correspondence to: Maria I. Bokarewa, e-mail: maria.bokarewa@rheuma.gu.se Keywords: Immune response, Immunity, Immunology and Microbiology Section, survivin, Bcl6, T-cells, autoimmunity, arthritis Received: May 19, 2015      Accepted: July 30, 2015      Published: August 12, 2015 ABSTRACT Follicular T helper (Tfh) cells are recognized by the expression of CXCR5 and the transcriptional regulator Bcl-6. Tfh cells control B cell maturation and antibody production, and if deregulated, may lead to autoimmunity. Here, we study the role of the proto-oncogene survivin in the formation of Tfh cells. We show that blood Tfh cells of patients with the autoimmune condition rheumatoid arthritis, have intracellular expression of survivin. Survivin was co-localized with Bcl-6 in the nuclei of CXCR5 + CD4 lymphocytes and was immunoprecipitated with the Bcl-6 responsive element of the target genes. Inhibition of survivin in arthritic mice led to the reduction of CXCR5 + Tfh cells and to low production of autoantibodies. Exposure to survivin activated STAT3 and induced enrichment of PD-1 + Bcl-6 + subset within Tfh cells. Collectively, our study demonstrates that survivin belongs to the Tfh cell phenotype and ensures their optimal function by regulating transcriptional activity of Bcl-6.