Dysregulated development of IL‐17‐ and IL‐21‐expressing follicular helper T cells and increased germinal center formation in the absence of RORγt

Abstract

Interleukin 17-producing helper T (Th17) cells have been widely defined by the lineage transcription factor retinoid-related orphan receptor (ROR)γt. Pathophysiologically, these cells play a crucial role in autoimmune diseases and have been linked to dysregulated germinal center (GC) reactions and autoantibody production. In this study, we used gene expression and flow cytometric analyses for the characterization of Rorγt(-/-) and Rorγt(-/-)Il21(RFP/+) mice to demonstrate a previously unknown transcriptional flexibility in the development of IL-17-producing Th-cell subsets. We found an accumulation of follicular Th (Tfh) cells by 5.2-fold, spontaneous 13-fold higher GC formation, decreased frequency of follicular Foxp3(+) T-regulatory (Treg) cells (50%), and a 3.4-fold increase in the number of proliferating follicular B cells in RORγt-deficient vs. wild-type mice. Dysregulated B-cell responses were associated with enhanced production of IL-17 (6.4-fold), IL-21 (2.2-fold), and B-cell-activating factor (BAFF) (2-fold) and were partially rescued by adoptive transfer of Treg cells. In an unexpected finding, we detected RORγt-independent IL-17 expression in ICOS(+)CXCR5(+)Tfh and in ICOS(+)CXCR5(-)Th cells. Based on the observed high Irf4 and Batf gene expression, we suggest that CD4(+) T-cell transcription factors other than RORγt can cooperatively induce differentiation of IL-17-producing Th cells, including Th17-like Tfh-cell subsets. We conclude that the occurrence of aberrant Tfh and follicular Treg cells support spontaneous GC formation and dysregulated B-cell responses in RORγt-deficient mice.

The T helper type 17/regulatory T cell paradigm in pregnancy

“…). Th17 cells are also a lineage of CD4 + T cells and are characterized by expressing the transcription factor retinoic acid receptor‐related orphan receptors and the cytokine IL‐17, among others. However, Th17 and Treg cells present a certain level of plasticity, meaning that distinct milieus account for distinct cell fate .…”

Fyn Plays a Pivotal Role in Fetomaternal Tolerance Through Regulation of Th17 Cells

“…Notably, the patterns of IRF4 expression observed in the current study were comparable with that of Fyn expression in both SA and normal pregnancy. IRF4 plays a crucial role in immune response and has been proposed as a decisive factor in the IL‐21‐mediated steps of Th17 development, by influencing Foxp3, ROR‐α and ROR‐γt expression . A recent study found that IRF4 expression was reduced during early stage of Th17 cell differentiation in the absence of Fyn .…”

The direct deleterious effect of Th17 cells in the nervous system compartment in multiple sclerosis and experimental autoimmune encephalomyelitis: one possible link between neuroinflammation and neurodegeneration

“…IL-17 and IL-21 are important for the formation of spontaneous ELS but also for the development of pathogenic autoantibodies in the CNS. The mechanism through which IL-17 is involved in this process is the following: IL17 upregulates signalling proteins that promote the capacity of follicular Th cells to form conjugates with B cells in the light zone of germinal centres in CNS and promotes follicular Th cells differentiation and stabilisation (21,22,24). Furthermore, the germinal centres include both follicular T cells and follicular regulatory T cells that maintain an optimal response in preventing the auto-emergence of the autoreactive B cells (25,26).…”

“…There is a close relationship between B cells and Th17 cells, leading to an elevated number of B cells and ELS as a mark for Th17 signature in MS (22,24). Th17 cells promote an inflammatory B cell response inside the CNS through the presence of infiltrating Th follicles (29).…”