A structural blueprint for interleukin-21 signal modulation

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 (Jun 2023)

A structural blueprint for interleukin-21 signal modulation

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

Affiliations

Gita C. Abhiraman: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
Theodora U.J. Bruun: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA
Nathanael A. Caveney: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA
Leon L. Su: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA
Robert A. Saxton: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA
Qian Yin: Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
Shaogeng Tang: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA
Mark M. Davis: Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
Kevin M. Jude: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
K. Christopher Garcia: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 6
p. 112657

Abstract

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Summary: Interleukin-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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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