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

Foxp3+ 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. ### Competing Interest Statement FMP received research support from Roche and Janssen, and consulting fees from GSK, Novartis and Genentech. CDB received research support from Roche, Janssen, Celsius Therapeutics, and consulting fees from GSK. HHU received research support or consultancy fees from Janssen, Eli Lilly, UCB Pharma, BMS/Celgene, MiroBio, Mestag and Omass. TT received research support from Celsius Therapeutics and consulting fees from AbbVie and ZuraBio. ST received research support from AbbVie, Buhlmann, Celgene, IOIBD, Janssen, Lilly, Pfizer, Takeda, UCB, Vifor and the Norman Collisson Foundation; consulting fees from AbbVie, Allergan, Αbiomics, Amgen, Arena, Asahi, Astellas, Biocare, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Buhlmann, Celgene, Chemocentryx, Cosmo, Enterome, Ferring, Giuliani SpA, GSK, Genentech, Immunocore, Immunometabolism, Indigo, Janssen, Lexicon, Lilly, Merck, MSD, Neovacs, Novartis, NovoNordisk, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Sensyne, Shire, Sigmoid Pharma, SynDermix, Takeda, Theravance, Tillotts, Topivert, UCB, Vhsquared, Vifor and Zeria; and speaker fees from AbbVie, Amgen, Biogen, Ferring, Janssen, Pfizer, Shire, Takeda and UCB (no stocks or share options). All other authors declare no competing interests.