Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease

Gut. 2019 May;68(5):814-828. doi: 10.1136/gutjnl-2017-315671. Epub 2018 May 30.


Objective: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.

Design: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.

Results: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.

Conclusions: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.

Keywords: apoptosis; crohn’s disease; intestinal T cells; mucosal immunology; tnf.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab / therapeutic use
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Crohn Disease / drug therapy
  • Crohn Disease / metabolism*
  • Crohn Disease / pathology
  • Drug Resistance*
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Infliximab / therapeutic use
  • Interleukin-17 / metabolism
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Middle Aged
  • Receptors, Interleukin / metabolism*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • T-Lymphocytes / physiology*
  • Young Adult


  • Gastrointestinal Agents
  • IL17A protein, human
  • IL23R protein, human
  • Interleukin-17
  • Receptors, Interleukin
  • Receptors, Tumor Necrosis Factor, Type II
  • Infliximab
  • Adalimumab