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Sci. Immunol., 2023 Mar 31;8(81):eadf2248 | https://doi.org/10.1126/sciimmunol.adf2248 The Transcription Factor Mef2d Regulates B:T Synapse–Dependent GC-TFH Differentiation and IL-21–Mediated Humoral Immunity

Ye-Ji Kim ¹, Jeein Oh ¹, Soohan Jung ¹, Chan Johng Kim ², Jinyong Choi ³, Yoon Kyung Jeon ⁴, Hyun Jik Kim ⁵, Ji-Won Kim ⁶, Chang-Hee Suh ⁶, Yoontae Lee ², Sin-Hyeog Im ^2,7,8, Shane Crotty ^9,10, Youn Soo Choi ^1,11,12*

¹Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
²Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Korea.
³Department of Microbiology, Department of Biomedicine & Health Sciences, College of Medicine, Catholic University of Korea, Seoul, Korea.
⁴Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
⁵Department of Otorhinolaryngology, Seoul National University Hospital, Seoul, Korea.
⁶Department of Rheumatology, Ajou University School of Medicine, Gyeonggi-do, Korea.
⁷ImmunoBiome Inc., Pohang, Korea.
⁸Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Korea.
⁹Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA.
¹⁰Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA, USA.
¹¹Department of Medicine, Seoul National University College of Medicine, Seoul, Korea.
¹²Transplantation Research Institute, Seoul National University Hospital, Seoul, Korea.

*Correspondingauthor: Youn Soo Choi

Abstract

Communication between CD4 T cells and cognate B cells is key for the former to fully mature into germinal center-T follicular helper (GC-T_FH) cells and for the latter to mount a CD4 T cell-dependent humoral immune response. Although this interaction occurs in a B:T synapse-dependent manner, how CD4 T cells transcriptionally regulate B:T synapse formation remains largely unknown. Here, we report that Mef2d, an isoform of the myocyte enhancer factor 2 (Mef2) transcription factor family, is a critical regulator of this process. In CD4 T cells, Mef2d negatively regulates expression of Sh2d1a, which encodes SLAM-associated protein (SAP), a critical regulator of B:T synapses. We found that Mef2d regulates Sh2d1a expression via DNA binding-dependent transcriptional repression, inhibiting SAP-dependent B:T synapse formation and preventing antigen-specific CD4 T cells from differentiating into GC-T_FH cells. Mef2d also impeded IL-21 production by CD4 T cells, an important B cell help signaling molecule, via direct repression of the Il21 gene. In contrast, CD4 T cell-specific disruption of Mef2d led to a substantial increase in GC-T_FH differentiation in response to protein immunization, concurrent with enhanced SAP expression. MEF2D mRNA expression inversely correlates with human systemic lupus erythematosus (SLE) patient autoimmune parameters, including circulating T_FH-like cell frequencies, autoantibodies, and SLEDAI scores. These findings highlight Mef2d as a pivotal rheostat in CD4 T cells for controlling GC formation and antibody production by B cells.

논문정보

형식Research article
게재일2023년 03월 (BRIC 등록일 2023-04-04)
연구진국내(교신)+국외 연구진
분야 의약학 > 면역의학

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