IL-21 is required for the maintenance and pathogenesis of murine Vγ4+ IL-17-producing γδT cells

Front Immunol. 2023 Aug 18:14:1211620. doi: 10.3389/fimmu.2023.1211620. eCollection 2023.


Murine IL-17-producing γδT (γδT17) cells are divided into two subsets: natural γδT17 (nγδT17) cells, whose development is restricted to the fetal thymus, and inducible γδT17 cells, which require antigen exposure for their IL-17 production and are presumed to develop from Rorc + Il17a - CCR9 + immature γδT17 cells in the adult thymus and whose T cell receptor (TCR) is biased toward Vγ4. Although IL-23 is known to be involved in developing γδT17 cells, the roles of other cytokines, such as IL-21, which is involved in developing Th17 cells like IL-23, in the development, maintenance, and pathophysiology of γδT17 cells remain unknown. Here, we show that IL-21 is dispensable for the fetal thymic development of nγδT17 cells but is required for the peripheral maintenance of Vγ4+nγδT17 cells. Upon stimulation with γδTCR, IL-1 plus IL-21 induces the proliferation of Vγ4+nγδT17 cells via STAT3 as effectively as IL-1 plus IL-23. Using bone marrow chimeric mice, we demonstrated that immature γδT17 cells are produced de novo in the adult mice from donor adult bone marrow cells and that IL-21 is dispensable for their development. Instead, IL-21 is required to expand newly induced Vγ4+γδT17 cells in the periphery upon immunization. Finally, using adoptive transfer experiments of γδT17 cells, we found that IL-21 receptors on γδT17 cells are involved in maintaining Vγ4+γδT17 cells, subsequent infiltration of Th17 cells into the spinal cord, and exacerbation of experimental autoimmune encephalomyelitis. Collectively, IL-21 plays a vital role in the maintenance and pathogenesis of Vγ4+γδT17 cells.

Keywords: IL-17; IL-21; Vγ4; experimental autoimmune encephalomyelitis; γδT cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Interleukin-1
  • Interleukin-17*
  • Interleukin-23
  • Interleukins*
  • Mice
  • T-Lymphocyte Subsets* / cytology


  • Interleukin-1
  • Interleukin-17
  • interleukin-21
  • Interleukin-23
  • Interleukins

Grants and funding

This work was supported by a Health Labor Sciences Research Grant on Allergic Disease and Immunology from the Ministry of Health, Labor, and Welfare of Japan, JST (Moonshot R&D) (Grant Number JPMJMS2025), and the Leading Graduate School Program at Chiba University from the Ministry of Education, Culture, Sports, Science, and Technology.