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
View: Text | PDF
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

×

Figure 7

IL-17 and IL-21 from Prdm1-CKO Tfh cells are responsible for the increased PB differentiation.

Options: View larger image (or click on image) Download as PowerPoint
IL-17 and IL-21 from Prdm1-CKO Tfh cells are responsible for the increas...
(A) B cells and Tfh were isolated from NP-CGG–immunized Prdm1-CKO mice, and they were cocultured in the presence of anti–IL-17 (10 μg/mL), anti–IL-21 (1 μg/mL) neutralizing Abs, or control IgG (10 μg/mL) as indicated in the figure. Proliferating B cells and IgG1 PB or IgM PB were identified by staining with GL7 and intracellular IgG1 and IgM within FVD-negative live B cells (n = 6, 3 independent experiments). (B) Supernatant from the A experiment was collected and IgG1 was quantified by ELISA (n = 4, 3 independent experiments). (C) B cells and Tfh were isolated from NP-CGG–immunized control mice, and they were cocultured in the presence of rmIL-17 (1 ng/mL) or rmIL-21 (1 ng/mL). Proliferating B cells, IgG1 PB, and IgM PB were identified by staining with GL7 and intracellular IgG1 and IgM (n = 6, 3 independent experiments). (D) Supernatant from the C experiment was collected and IgG1 was measured by ELISA. (E) The difference in IgG1 PB was calculated as follow: for CTL Tfh (first 3 columns), (IgG1 PB from rm cytokine-treated groups IgG1 PB of no exogenous cytokine group)/IgG1 PB of no exogenous cytokine group x 100; for Prdm1-CKO Tfh (last 3 columns), and (IgG1 PB from neutralizing IgG–treated group IgG1 PB of ctl-IgG–treated group)/IgG1 PB of ctl-IgG–treated group x 100. Each dot represents an individual mouse, and the bar graph represents the mean (n = 6, 3 independent experiments). A 1-way ANOVA with Dunnett’s correction was used.