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CD30/CD30L is critical for Tfh cell differentiation and promotes antibody production against Plasmodium yoelii infection

ABSTRACT: Host resistance to malaria parasite infection relies on the establishment of a moderate and sequential adaptive immune response. The production of specific antibodies is critical for parasite clearance. CD30 and CD30L are respective members of the tumor necrosis factor (TNF) receptor superfamily and TNF superfamily; and are expressed on the surface of various immune cells and tissue cells. In mice infected with a non-lethal Plasmodium yoelii strain, CD30/CD30L expression was significantly increased. Using CD30L-deficient (CD30L−/−) mice, we found that the CD30/CD30L interaction played a crucial role in the activation of T follicular helper (Tfh) cells and germinal center (GC) B cells. During P. yoelii infection, CD30L−/− mice developed a weaker humoral response with reduced differentiation of Tfh cells, decreased secretion of IL-21, impaired formation of GCs, a lower number of antibody-secreting cells, and reduced production of antibodies. Supplementing the CD30L−/− mice with recombinant IL-21 (rIL-21) restored the number and proliferation of Tfh cells, but it did not completely restore the humoral immune response. The expression of IL-21R on CD4+ T cells and B cells in CD30L−/− mice during infection was significantly lower than that in wild-type mice; and supplementation with rIL-21 did not increase IL-21R expression on T and B cells. Therefore, we conclude that the CD30/CD30L receptor-ligand pair are key molecules for Tfh cell differentiation and maintenance of the Tfh-GC B cell response, which are needed for the establishment of humoral immunity against P. yoelii blood-stage infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE272007 | GEO | 2025/06/12

REPOSITORIES: GEO

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Project description:Follicular T helper cells (Tfh) are critical for providing help to B cells for germinal center (GC) formation. Mutations affecting SAP prevent GC formation due to defective T:B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent “Tfh-like” cells that expressed IL-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts substantially better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, other Th cell populations could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cells, supporting the concept of plasticity between Tfh and other Th populations. We describe the in vitro differentiation of functionally competent IL-21-producing cells with Tfh-like properties. Importantly, transfer of low numbers of these cells induced GC formation in SAP-deficient hosts more effectively than other in vitro differentiated Th cells, suggesting they represent bona fide Tfh cell precursors. We have chosen the name “Tfh-like” cells for these in vitro differentiated IL-21 producing cells as they exhibit Tfh characteristics, but do not reside within B cell follicles. SAP-deficient Tfh-like cells were virtually indistinguishable from WT, yet nonetheless, failed to effectively contribute to Tfh cells and rescue GC formation in vivo. Evaluation of cytokine production as well as epigenetic chromatin modifications of genes encoding Th cell-specific transcription factors from either in vitro-generated Tfh-like cells or Tfh cells isolated directly ex vivo provided evidence for plasticity between Tfh-like and other Th cell populations. Our results provide insight into the requirements for differentiation and plasticity of Tfh cells, which are critical for the generation of effective long-term humoral immunity. RNA was prepared from subconfluent asynchronously proliferating cells using TRIZOL and purified by RNeasy MinElute Cleanup kit (Qiagen). Hybridization to Affymetrix GeneChip Mouse Genome 430 2.0 arrays was used to generate gene expression profiles of WT Tfh-like and SAP-deficient Tfh-like cells.

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CD30/CD30L is critical for Tfh cell differentiation and promotes antibody production against Plasmodium yoelii infection

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