CD4 T Cell–Derived IL-21 Is Critical for Sustaining Plasmodium Infection–Induced Germinal Center Responses and Promoting the Selection of Memory B Cells with Recall Potential

Development of Plasmodium-specific humoral immunity is critically dependent on CD4 Th cell responses and germinal center (GC) reactions during blood-stage Plasmodium infection. IL-21, a cytokine primarily produced by CD4 T cells, is an essential regulator of affinity maturation, isotype class-switching, B cell differentiation, and maintenance of GC reactions in response to many infection and immunization models. In models of experimental malaria, mice deficient in IL-21 or its receptor IL-21R fail to develop memory B cell populations and are not protected against secondary infection. However, whether sustained IL-21 signaling in ongoing GCs is required for maintaining GC magnitude, organization, and output is unclear. In this study, we report that CD4+ Th cells maintain IL-21 expression after resolution of primary Plasmodium yoelii infection. We generated an inducible knockout mouse model that enabled cell type-specific and timed deletion of IL-21 in peripheral, mature CD4 T cells. We found that persistence of IL-21 signaling in active GCs had no impact on the magnitude of GC reactions or their capacity to produce memory B cell populations. However, the memory B cells generated in the absence of IL-21 exhibited reduced recall function upon challenge. Our data support that IL-21 prevents premature cellular dissolution within the GC and promotes stringency of selective pressures during B cell fate determination required to produce high-quality Plasmodium-specific memory B cells. These data are additionally consistent with a temporal requirement for IL-21 in fine-tuning humoral immune memory responses during experimental malaria.

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Work Title CD4 T Cell–Derived IL-21 Is Critical for Sustaining Plasmodium Infection–Induced Germinal Center Responses and Promoting the Selection of Memory B Cells with Recall Potential
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Open Access
Creators
  1. Jordan T. Johnson
  2. Fionna A. Surette
  3. Graham R. Ausdal
  4. Manan Shah
  5. Allen M. Minns
  6. Scott E. Lindner
  7. Ryan A. Zander
  8. Noah S. Butler
Keyword
  1. Plasmodium
  2. IL-21
  3. T follicular helper cell
  4. Germinal center
  5. Memory B cell
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. Journal of Immunology
Publication Date March 13, 2024
Publisher Identifier (DOI)
  1. https://doi.org/10.4049/jimmunol.2300683
Deposited October 07, 2024

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Version 1
published

  • Created
  • Added Johnson_Surette_Combined_PDF.pdf
  • Added Creator Jordan T. Johnson
  • Added Creator Fionna A. Surette
  • Added Creator Graham R. Ausdal
  • Added Creator Manan Shah
  • Added Creator Allen M. Minns
  • Added Creator Scott E. Lindner
  • Added Creator Ryan A. Zander
  • Added Creator Noah S. Butler
  • Published
  • Updated
  • Updated Keyword, Publication Date Show Changes
    Keyword
    • Plasmodium, IL-21, T follicular helper cell, Germinal center, Memory B cell
    Publication Date
    • 2024-05-01
    • 2024-03-13