Presence, function, and regulation of IL‐17F‐expressing human CD4⁺ T cells

Abstract

The pro‐inflammatory cytokine IL‐17A has been implicated in the immunopathology of inflammatory arthritis. IL‐17F bears 50% homology to IL‐17A and has recently been suggested to play a role in inflammation. We investigated the induction and cytokine profile of IL‐17F+ CD4+ T cells, and how IL‐17F may contribute to inflammation. Upon culture of healthy donor CD4+ T cells with IL‐1β, IL‐23, anti‐CD3, and anti‐CD28 mAb, both IL‐17A and IL‐17F‐expressing cells were detected. In comparison to IL‐17A+IL‐17F− CD4+ T cells, IL‐17F+IL‐17A− and IL‐17A+IL‐17F+ CD4+ T cells contained lower proportions of IL‐10‐expressing and GM‐CSF‐expressing cells and higher proportions of IFN‐γ‐expressing cells. Titration of anti‐CD28 mAb revealed that strong co‐stimulation increased IL‐17F+IL‐17A− and IL‐17A+IL‐17F+ CD4+ T cell frequencies, whereas IL‐17A+IL‐17F− CD4+ T cell frequencies decreased. This was partly mediated via an IL‐2‐dependent mechanism. Addition of IL‐17A, IL‐17F, and TNF‐α to synovial fibroblasts from patients with inflammatory arthritis resulted in significant production of IL‐6 and IL‐8, which was reduced to a larger extent by combined blockade of IL‐17A and IL‐17F than blockade of IL‐17A alone. Our data indicate that IL‐17A and IL‐17F are differentially regulated upon T cell co‐stimulation, and that dual blockade of IL‐17A and IL‐17F reduces inflammation more effectively than IL‐17A blockade alone.

Interleukin (IL)-12 and IL-18 Synergize to Promote MAIT Cell IL-17A and IL-17F Production Independently of IL-23 Signaling

“…These observations suggest IL-17A and IL-17F may be differentially regulated cytokines. Indeed, STAT5 and TNFAIP3 have been shown to differentially influence the production of these two related isoforms (46)(47)(48). These data may explain why IL-17F is also the dominant IL-17 isoform expressed in inflammatory diseases such as psoriasis, psoriatic arthritis and ankylosing spondylitis where IL-17F levels are measured to be at least 30-fold higher than IL-17A (49).…”

Bimekizumab, a Novel Humanized IgG1 Antibody That Neutralizes Both IL-17A and IL-17F

“…Both IL-17A and IL-17F cytokines are expressed by Th17 cells, as well as additional immune cell types, including CD8 T cells, natural killer T cells, lymphoid tissue inducer cells, innate lymphoid cells and γδ T cells ( 11 ). Although common pathways are involved in the differentiation of Th17 cells, emerging data suggest that the regulation of IL-17A expression is distinct from that of IL-17F ( 12 ). IL-17A has a stronger affinity for the IL-17RA/RC complex, and thus promotes a greater induction of pro-inflammatory genes than IL-17F.…”

An Overview of Bimekizumab for the Treatment of Psoriatic Arthritis: The Evidence so Far

“… 21 Dual neutralization of both IL-17A and IL-17F (using bimekizumab) resulted in greater downregulation of pro-inflammatory cytokine production than a single blockade in synovial fibroblasts. 9 , 19 Critically, in in vitro models, anti-TNF blockade alone did not reduce the production of IL-8 as much as both IL-17A and F neutralization or even just anti-IL17A alone. 9 , 19 In in vitro models of human periosteum dual blockade of IL-17A and F was also more effective in suppressing osteogenic differentiation than the blockade of either cytokine individually.…”

“… 9 IL-17A seems to be the most pro-inflammatory of the two cytokines. 9 , 19 However, despite some inconsistencies in the literature regarding IL-17F detection levels which might be attributable to differences in methodology, 19 IL-17F levels have been reported to be 30–50 times higher in some cytokine microenvironments, such as in psoriatic skin lesions of PsA patients 20 or the synovium, 21 which might dilute differences in relative potency. Additionally, IL-17F seems to be significantly increased in the synovium of PsA compared to osteoarthritis (OA) patients, unlike IL-17A.…”