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

doi:10.1016/j.celrep.2023.112657

A structural blueprint for interleukin-21 signal modulation

Cell Rep. 2023 Jun 27;42(6):112657. doi: 10.1016/j.celrep.2023.112657. Epub 2023 Jun 19.

Authors

Affiliations

¹ 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.
² Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
³ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
⁴ 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.
⁵ 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.
⁶ 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. Electronic address: kcgarcia@stanford.edu.

Abstract

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.

Keywords: CP: Immunology; CP: Molecular biology; IL-21; cytokine; germinal center; humoral immunity; immunology; receptor; signaling; signaling complex; structural biology; vaccination.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cryoelectron Microscopy
Crystallography, X-Ray
Germinal Center*
Humans
Interleukin-2
Interleukins*

Substances

interleukin-21
Interleukins
Interleukin-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding