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

Jordan T. Johnson, Fionna A. Surette, Graham R. Ausdal, Manan Shah, Allen M. Minns, Scott E. Lindner, Ryan A. Zander, Noah S. Butler

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1467-1478
Number of pages12
JournalJournal of Immunology
Issue number9
StatePublished - May 1 2024

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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