IL-17–producing follicular Th cells enhance plasma cell differentiation in lupus-prone mice
Vera Kim, … , Betty Diamond, Sun Jung Kim
Vera Kim, … , Betty Diamond, Sun Jung Kim
Published June 8, 2022
Citation Information: JCI Insight. 2022;7(11):e157332. https://doi.org/10.1172/jci.insight.157332.
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Research Article Immunology

IL-17–producing follicular Th cells enhance plasma cell differentiation in lupus-prone mice

Abstract

Follicular Th (Tfh) cells are key CD4+ Th cells involved in regulating B cell differentiation in the germinal center. Mice with conditional KO (CKO) of B lymphocyte-induced maturation protein-1 (BLIMP-1) expression in CD11chi DCs (Prdm1 CKO) spontaneously develop a lupus-like disease. We found an increase in the number of Tfh cells in secondary lymphoid organs in lupus-prone Prdm1-CKO mice. B cells stimulated with Tfh cells become Ab-secreting cells (ASCs); there was an increase in ASC differentiation mediated by Tfh cells from Prdm1-CKO mice compared with Tfh cells from control mice. This was mainly due to the increased expression of molecules within the IL-23/IL-17 pathway in Tfh cells from Prdm1-CKO mice. There was an increased frequency of IL-17A+ Tfh cells in Prdm1-CKO mice. These Tfh cells secrete IL-17A and an increased amount of IL-21. Furthermore, neutralizing IL-17A and IL-21 reduced ASC differentiation induced by Tfh cells. Lastly, we found the expression of IL-1β and IL-6 was increased in BLIMP-1–deficient DCs, which are key for Th17 induction. Altogether, the lack of BLIMP-1 expression in DCs induces not only an increased number of Tfh cells, but also functionally distinct Tfh cells that lead to increased ASC differentiation.

Authors

Vera Kim, Kyungwoo Lee, Hong Tian, Su Hwa Jang, Betty Diamond, Sun Jung Kim

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Figure 1

Increased IgG1+ PB differentiation by Tfh cells from Prdm1-CKO mice.

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Increased IgG1+ PB differentiation by Tfh cells from Prdm1-CKO mice. FOX...
FOXP3-GFP, Prdm1-CKO or FOXP3-GFP, and control mice (6- to 8-week-old females) were immunized with NP-CGG and live B cells (CD19+), Tfh (TCRβ+CD4+CXCR5+PD1+FOXP3–), and Tfr (TCRβ+CD4+CXCR5+PD1+FOXP3+) cells were isolated by cell sorter. (A) Isolated B cells were cultured alone, with Tfh, or with Tfh and Tfr in the presence of anti-IgM with anti-CD3 antibodies or NP-OVA with anti-CD3 antibodies as indicated in the figure (legend indicates the source of T cells; open circle is CTL mice and closed circle is Prdm1-CKO mice). After 7 days of culture, isotype-specific PB was identified by staining of GL7, IgG1 (upper graph), and IgM (bottom graph) (n = 9 for both CTL and KO). (B) IgG1 PB differentiation was performed with B cells from CTL mice or Prdm1-CKO mice (n = 9 for both CTL and KO). (C) Number of IgG1-secreting PB was quantified by ELISpot. A representative image of spots from 4 independent experiments (duplicates of each culture condition) and the graphs indicate the number of spots (on the left) and the mean spot size (on the right) (n = 4). (D) Secreted IgG1 in the supernatant was measured by ELISA. Each dot represents an individual mouse in A, B, and D or an individual experiment in C. Bar indicates the mean (n = 12) from 3 independent experiments. A 1-way ANOVA with Bonferroni correction was used for statistical analyses.