Gita C Abhiraman, Theodora U J Bruun, Nathanael A Caveney, Leon L Su, Robert A Saxton, Qian Yin, Shaogeng Tang, Mark M Davis, Kevin M Jude, K Christopher Garcia
Cell reports 2023 Jun 27Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and association with autoimmune disease. To better understand the structural basis of IL-21 signaling, we determine the structure of the IL-21-IL-21R-γc ternary signaling complex by X-ray crystallography and a structure of a dimer of trimeric complexes using cryo-electron microscopy. Guided by the structure, we design analogs of IL-21 by introducing substitutions to the IL-21-γc interface. These IL-21 analogs act as partial agonists that modulate downstream activation of pS6, pSTAT3, and pSTAT1. These analogs exhibit differential activity on T and B cell subsets and modulate antibody production in human tonsil organoids. These results clarify the structural basis of IL-21 signaling and offer a potential strategy for tunable manipulation of humoral immunity. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Gita C Abhiraman, Theodora U J Bruun, Nathanael A Caveney, Leon L Su, Robert A Saxton, Qian Yin, Shaogeng Tang, Mark M Davis, Kevin M Jude, K Christopher Garcia. A structural blueprint for interleukin-21 signal modulation. Cell reports. 2023 Jun 27;42(6):112657
PMID: 37339051
View Full Text