Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

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Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Authors and Affiliations

Sungjun Park^1,*, Seungwon Lee^2,*, Choong-Gu Lee^3,*, Guk Yeol Park¹, Hyebeen Hong¹, Jeon-Soo Lee¹, Young Min Kim¹, Sung Bae Lee⁴, Daehee Hwang⁵, Youn Soo Choi^6,7, John D. Fryer⁸, Sin-Hyeog Im^1,2,3, Seung-Woo Lee^1,2 & Yoontae Lee^1,2¹Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 73673, Republic of Korea. ²Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 73673, Republic of Korea. ³Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Gyeongbuk 73673, Republic of Korea. ⁴Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea. ⁵ Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 42988, Republic of Korea. 6Department of Biomedical Sciences, Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. ⁷ Transplantation Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. ⁸Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
^* These authors contributed equally to this work.

Correspondence to Sin-Hyeog Im or Seung-Woo Lee or Yoontae Lee

Abstract
High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (T_FH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of T_FH cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null T_FH cells and knockdown of Etv5 suppresses the enhanced TFH cell differentiation in Cic-deficient CD4⁺ T cells, suggesting that Etv5 is a critical CIC target gene in T_FH cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC-ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates T_FH cell development and autoimmunity.



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