IL-17RA Is Essential for Optimal Localization of Follicular Th Cells in the Germinal Center Light Zone To Promote Autoantibody-Producing B Cells

Abstract

Germinal centers provide a microenvironment that promotes and regulates the interactions of B-cells with follicular T-helper cells (TFH). Here we show that there are significantly higher frequencies of CXCR5+ICOS+TFH cells in autoimmune BXD2 mice, and these cells express both interleukin (IL)-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra−/− mice, the majority of CXCR5+ TFH cells from BXD2-Il17ra−/− mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra−/−, disrupted TFH–B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling (RGS)16 to promote the ability of TFH to form conjugates with B cells which was abolished in TFH cells from BXD2-Rgs16−/− mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on post-differentiated IL-17RA+ TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.

TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity

“…Moreover, in agreement with high levels of IgG2 in the blood of TGF-βR-KO mice (28), we noticed that Tfh cells that developed in an unrestrained manner in the absence of TGF-β control massively produced IFN-γ in contrast to basal Tfh cells from TGF-βR-WT mice (Supplemental Figure 1C). Furthermore, we did not detect IL-17 (data not shown), a cytokine that has been implicated in pathogenic GC formation in some circumstances (31). jci.org Volume 124 Number 10 October 2014 CD44 hi , CD122, and Ly49 that have been shown to repress spontaneous development of Tfh cells by inducing their apoptotic death, thereby efficiently contributing to the control of autoimmune diseases in both mice and humans (20,21,37).…”

R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity

“…GCs from BXD2 mice have increased numbers of plasmablasts, expression of B cell differentiation genes, and T FH populations. B cell and T cell abnormalities in this strain are rescued by gene deletion of Rgs13 or Rgs16, respectively, which is accompanied by significantly reduced numbers of B-T cell conjugates in GCs and autoantibody titers (71,72). Given RGS13's ability to blunt chemokine-mediated migration, these studies suggest that IL-17 promotes autoimmunity in BXD2 mice by prolonging transit of B and T cells through GCs, resulting in excess antibody production.…”

Interleukin-17 Enhances Germinal Center Formation and Immunoglobulin G1 Production in Mice

“…The authors argued that IL-17 induced regulator of G-protein signaling proteins, which suppressed migration, and consequently stabilized germinal center (GC) B cells to elicit proper GC reaction [11,12]. In line with this, it was reported that Th17 cells transferred into wild type (WT) C57BL/6 mice induced GC formation, which was abrogated in IL-17 RA knockout (KO) mice [13].…”

“…Xie and colleagues [11,12] reported the first evidence that IL-17 affected antibody production by B cells in an autoimmune BXD2 mouse model. The authors argued that IL-17 induced regulator of G-protein signaling proteins, which suppressed migration, and consequently stabilized germinal center (GC) B cells to elicit proper GC reaction [11,12].…”