IL-23 p19 Blockade and Th17 Signaling

How does IL-23 p19 blockade by risankizumab alter Th17 and IL-22 signaling?

I'll pull up mechanistic studies and trial data on risankizumab's effects on Th17 and IL-22 signaling pathways.

Mechanism Overview

Risankizumab binds the p19 subunit of IL-23 and competitively blocks its interaction with the IL-23Rα receptor subunit, preventing downstream JAK2/TYK2-mediated STAT3 phosphorylation. This interrupts IL-23's core function as the survival and amplification signal for Th17 (and Th22) cells. What's emerged from translational work is that the effects on the Th17 compartment are not uniform — risankizumab selectively targets pathogenic subsets while leaving others relatively intact, which distinguishes its mechanism from direct IL-17A blockade.

Selective suppression of pathogenic T17 subsets

A 2025 single-cell RNA-seq study by Kim et al. in the Journal of Allergy and Clinical Immunology mapped six distinct T17 subsets in psoriatic skin using 93 single-cell libraries. Two subsets — an IL-17A⁺IFN-γ⁺ population and an IL-17F⁺IL-10⁻ population — expressed the IL-23 receptor and were specifically downregulated by risankizumab. A third subset co-expressing both IL-17A and IL-17F did not express the IL-23R, and its frequency actually increased after IL-23 blockade. This selectivity matters: the IL-23R-expressing subsets appear to drive tissue pathology, while the non-IL-23R subsets may contribute to barrier immunity. Additionally, TNFAIP3 (a negative regulator of IL-17 signaling) was upregulated in myeloid cells more strongly after IL-23 inhibition than after IL-17A blockade — suggesting a broader anti-inflammatory feedback that IL-17A blockade doesn't engage.

In Crohn's disease, the same selectivity principle plays out in a distinct cell subset. Noviello et al. (2024, Journal of Crohn's & Colitis), drawing from the SEQUENCE trial, identified a tissue-resident CCR6⁺CXCR3⁻CCR5⁺ pathogenic Th17 (pTh17) subset that infiltrates the IEL layer via CD103/E-cadherin binding and is specifically activated by Adherent-Invasive E. coli. Risankizumab selectively downregulated this pTh17 subset (in both lamina propria and IEL compartments) without affecting conventional cTh17 cells. Ustekinumab reduced Th1/17 subsets instead, not pTh17 — mechanistically explaining its different clinical profile.

Effects on IL-22 signaling

IL-23 is required for IL-22 production in Th22 cells and some Th17 cells, so p19 blockade reduces IL-22 levels, but the relationship is context-dependent. A phase II biopsy substudy in Crohn's disease (Visvanathan et al., Journal of Crohn's & Colitis, 2018) used RNA-seq on colonic and ileal biopsies from 106 patients and found significant downregulation of over 1,800 genes by week 12, with the IL-23/IL-17 axis and Th1 pathway among the most affected. Plasma IL-22 fell significantly versus placebo. However, a biomarker analysis from the same phase II study reported that neither baseline IL-22 levels nor the degree of IL-22 reduction predicted clinical response — suggesting IL-22 is a downstream marker of pathway activity, not a driver of response per se.

In psoriatic skin, the same Visvanathan et al. study comparing risankizumab to ustekinumab (2019, JACI) showed that risankizumab by week 4 more strongly suppressed keratinocyte, epidermal, and monocyte gene expression, and achieved superior histopathologic improvement (54–69% of risankizumab-treated patients graded as "excellent" versus 29% with ustekinumab). This broader transcriptomic reach downstream of IL-22 suppression — including keratinocyte hyperproliferation markers like K16 and Ki67, and antimicrobial peptides like S100A7 and β-defensin 2 — reflects IL-22's known role in driving epidermal pathology.

In skin, Favaro et al. (2025, Journal of Dermatological Science) tracked circulating T-cell populations over 52 weeks of risankizumab treatment and found that CD8⁺IL-17⁺ and CD8⁺IL-22⁺ T cells decreased with treatment, as did CD3⁺MAIT IL-22⁺ cells — the latter being relevant to psoriatic arthritis comorbidity. Tregs increased and the IL-17⁺CD4⁺/Treg ratio fell, suggesting a rebalancing of the effector/regulatory axis.

Comparison with broader IL-23 blockade and non-clinical mechanistic work

Non-clinical head-to-head comparisons (Zhou et al., 2019, JID) established that in an IL-23-driven mouse ear-swelling model, risankizumab outperformed guselkumab, ustekinumab, and tildrakizumab at reducing IL-17, IL-22, and keratinocyte gene expression at low doses, attributable in part to risankizumab's large epitope surface area and high-affinity binding that completely blocks the p19/IL-23Rα interaction. Tildrakizumab was notably described as a negative allosteric modulator rather than a competitive blocker and was less effective in vivo.

A theme across the mechanistic literature is that upstream IL-23 blockade achieves something that downstream IL-17A blockade does not: it removes the survival signal that maintains ROR-γt⁺ Th17 cells while also dampening the IL-22 axis and enabling Treg recovery. The ROR-γt dependence of this pathway has been confirmed in preclinical models where pharmacological ROR-γt inhibition recapitulated the transcriptomic changes seen with IL-23 blockade. The distinction from IL-17A blockade — which cuts one effector branch but leaves IL-23-driven Th17 expansion and IL-22 production intact — likely underlies risankizumab's durability and the lower rates of IBD induction seen with p19 inhibitors compared to IL-17A blockers.

This picture comes from a set of initial searches across mechanistic, transcriptomic, and biomarker studies; deeper work through extended thinking could pull in additional data on STAT3 signaling quantification, ILC3 contributions to IL-22 in the gut, and emerging single-cell datasets.