Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice

By H. Hsu, Pingar Yang, John L. Wang, Qi Wu, Riley C. Myers, Jian Chen, J. Yi, T. Guentert, A. Tousson, A. L. Stanus and 8 more. Nature Immunology, 2008

748 citations recorded by the source corpus.

Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/7c94625b5ad73e0f47efc0c46d66c2f055929802

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Citations in the corpus

Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response (2011, background): “Dysregulation of the T FH cell population has been previously shown to result in autoimmunit”
Costimulatory molecule ICOS plays a critical role in the development of TH-17 and follicular T-helper cells by regulating c-Maf expression and IL-21 production (2008, background): “The crucial function of ICOS in germinal center development and the generation of T FH cells is well established; ICOS- or ICOS-L-deficient mice develop fewer and smaller germinal centers after immunization, associated with impaired T cell–dependent B cell responses and impaired isotype class switc”
TH17 cells in development: an updated view of their molecular identity and genetic programming (2008, background): “In addition, IL-17 was reported to promote germinal-centre reactions in a mouse model of an SLE-like diseas”
The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling (2011, background): “Furthermore, disruption of IL-17 affects the formation of germinal center”
The biological functions of T helper 17 cell effector cytokines in inflammation. (2008, positive): “It has also recently been demonstrated that IL-17 regulates germinal-center formation, as well as auto-antibody production (Hsu et al., 2008).”
Opposing regulation of the Il17 locus through direct, reciprocal actions of STAT3 and STAT5 (2011, background): “Along with the T H 17 cell–associated cytokine IL-21, IL-17 provides help to B cell”
Orchestrating the orchestrators: chemokines in control of T cell traffic (2008, background): “Other work suggests that splenic T H -17 cells might also drive autoimmune disease independently of their proinflammatory effect”
FOLLICULAR HELPER T CELLS: LINEAGE AND LOCATION (2009, background): “Further to this notion, IL-17 production was induced preferentially from CXCR5+ICOShi Tfh cells after MOG peptide in CFA immunization (Bauquet et al., 2008).”
IL-17 and Th17 Cells. (2009, background): “Both Th17 and T follicular helper cells are a major source of IL-21, and therefore both may play an important role in setting up productive GC reactions (187).”
Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells (2010, background): “recently reported a direct impact of IL-17 on GC formation in the BXD2 mouse strain (Hsu et al., 2008).”
IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism (2010, background): “…mice did not distinguish between IL-21 acting directly on the B cells or having an effect via, for example, Tfh or Th17 cells, both of which are known to respond to and produce IL-21 and both of which are implicated in GC development (Hsu et al., 2008; Nurieva et al., 2008; Vogelzang et al., 2008).”
The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. (2009, background): “Also, there is evidence that accumulation of 464 Immunity 31, 457–468, September 18, 2009 ª2009 Elsevier Inc. IL-17-producing cells in GCs is associated with autoimmunity in BXD2 mice (Hsu et al., 2008).”