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Updated: Jul 26, 2025

A Strategy for the Study of IL-9-Producing Lymphoid Cells in the Nippostrongylus brasiliensis Infection Model
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A structural blueprint for interleukin-21 signal modulation.

Gita C Abhiraman1, Theodora U J Bruun2, Nathanael A Caveney3

  • 1Department 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.

Cell Reports
|June 20, 2023
PubMed
Summary

Researchers determined the structure of Interleukin-21 (IL-21) signaling complexes. They designed novel IL-21 analogs that modulate immune responses, offering potential for tunable manipulation of humoral immunity.

Keywords:
CP: ImmunologyCP: Molecular biologyIL-21cytokinegerminal centerhumoral immunityimmunologyreceptorsignalingsignaling complexstructural biologyvaccination

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Area of Science:

  • Immunology
  • Structural Biology
  • Molecular Biology

Background:

  • Interleukin-21 (IL-21) is crucial for immunological memory and germinal center reactions.
  • Clinical applications of IL-21 are limited by its pleiotropy and autoimmune associations.

Purpose of the Study:

  • To elucidate the structural basis of IL-21 signaling.
  • To design IL-21 analogs with modulated immune activity.

Main Methods:

  • X-ray crystallography and cryo-electron microscopy were used to determine the structure of IL-21 signaling complexes.
  • Structure-guided design of IL-21 analogs with substitutions at the IL-21-γc interface.

Main Results:

  • The study determined the structure of the IL-21-IL-21R-γc ternary complex and a dimer of trimeric complexes.
  • Designed IL-21 analogs function as partial agonists, modulating pS6, pSTAT3, and pSTAT1 activation.
  • These analogs demonstrated differential effects on T and B cell subsets and antibody production in human tonsil organoids.

Conclusions:

  • The findings clarify the structural mechanisms underlying IL-21 signaling.
  • Developed IL-21 analogs offer a strategy for precise control of humoral immunity.