Anti-TNF-induced IL-27 modulates regulatory T cell responses in patients with IBD that respond to therapy

Abstract

ABSTRACTFoxp3+regulatory T (Treg) cells are essential for maintaining immune homeostasis. Breakdown of homeostasis can lead to inflammatory bowel disease (IBD), a condition characterised by chronic inflammation of the gastrointestinal tract. Changes in the composition and function of Treg subsets can underlie IBD in some patients. Moreover, anti-TNF, the most common first-line biologic in the treatment of IBD, may mediate its anti-inflammatory effects through modulating Treg responses. However, up to 40% of patients with IBD exhibit primary non-responsiveness to anti-TNF therapy. The molecular and cellular mechanisms associated with anti-TNF resistance have yet to be fully elucidated. Furthermore, it is not clear whether Treg responses contribute to this state. Herein, we used multi-modal profiling of Tregs from both the tissue and blood of patients with IBD before and after anti-TNF therapy. In contrast to non-responders to therapy, we found increased PD-1 expression on circulating HLA-DRB1hiTregs from patients responding to anti-TNF. Anti-TNF induced IL-27 production by circulating and tissue mononuclear phagocytes (MNPs) through Fc gamma receptor activation, and in turn increased the expression of PD-1 on Tregs in a STAT3-dependent manner. Expression of selected genes known to be up-regulated upon IL-27 stimulation was increased after anti-TNF therapy in circulating Tregs from responders. We further demonstrated that IL-27 augmented the functional suppressive capacity of Tregs from responders but not from non-responders. Together, these data reveal anti-TNF therapy-induced MNP-Treg interaction and provide evidence that the IL-27/PD-1+Treg axis is associated with anti-TNF response in IBD.ONE SENTENCE SUMMARYAnti-TNF response in IBD is linked to an increase of PD-1 expression on circulating Tregs mediated by IL-27 induction via Fc gamma receptor activation.