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IL-17–producing follicular Th cells enhance plasma cell differentiation in lupus-prone mice
Vera Kim, Kyungwoo Lee, Hong Tian, Su Hwa Jang, Betty Diamond, Sun Jung Kim
Vera Kim, Kyungwoo Lee, Hong Tian, Su Hwa Jang, Betty Diamond, Sun Jung Kim
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Research Article Immunology

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

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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 5

Increased activation of inflammasome and production of IL-1β and IL-6 in BLIMP-1–deficient DCs.

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Increased activation of inflammasome and production of IL-1β and IL-6 in...
Prdm1-CKO and control mice (6- to 8-week-old females) were immunized with NP-CGG, and spleens were collected at day 7 following immunization. cDCs (CD11chiMHCIIhiCD11b+) were purified by cell sorter and cultured for 4 hours, after which cells and supernatant were collected. (A) Transcript of cytokines were measured from the cells by qPCR, and (B) secreted cytokines in the supernatant were measured by MSD in 3 independent experiments (n = 4 for CTL and n = 5 or 6 for KO). (C) To measure the activation of the inflammasome pathway, transcripts of Nlrp3 in cDCs were measured by qPCR and caspase-1 activity was measured by FAM-FLICA in cDCs. Each dot represents an individual mouse, and the bar represents the mean (n = 4 for CTL and n = 5 for KO) from 3 independent experiments. (D) STAT3 activation in naive T cells was measured. Naive CD4+ T cells and DCs were prepared, and T cells were stimulated with control DCs (CTL) or BLIMP-1–deficient DCs (KO) or rmIL-6 for 15 minutes. Neutralizing Abs of IL-6/IL-1β or control IgG were added during the stimulation in the indicated conditions. After the stimulation, cells were fixed and p-STAT3 and total STAT3 were measured by flow cytometry. Representative histogram images are on the upper row. A red line was drawn based on T alone without stimulation. Each dot represents an individual animal, and the bar represents the mean from 3 independent experiments (n = 12). An unpaired 2-tailed Student’s t test (Mann-Whitney) was used for A–C and 1-way ANOVA with Dunnett’s correction was used for D.

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