Treg are endowed with immunosuppressive activities and have been proposed as promising targets for the therapy of autoimmune diseases. As the suppressive capacity of Treg depends on their migration into the affected tissues, we tested here whether modulation of Treg homing would enhance their capacity to suppress inflammation in mouse models of inflammatory bowel disease. Retinoic acid (RA) was used to induce the gut‐specific homing receptor α4β7 efficiently and, to some extent, the chemokine receptor CCR9 on in vitro expanded Treg. Upon transfer, RA‐treated Treg were indeed more potent suppressors in an acute, small intestinal inflammation model, compared with Treg stimulated without RA. By contrast, the efficacy of Treg to resolve an established, chronic inflammation of the colon in the transfer colitis model was not affected by RA‐treatment. In the latter model, a rapid loss of RA‐induced α4β7 expression and de novo induction of α4β7 on previously negative cells was observed on transferred Treg, which implies that Treg acquire gut‐seeking properties in vivo under inflammatory and/or lymphopenic conditions. Together, our data show that the induction of appropriate homing properties prior to transfer increases the protective potential of adoptively transferred Treg in acute, but not in chronic, inflammatory disorders of the gut.

Gut-activated T cells migrating into the liver can cause extraintestinal manifestations of inflammatory bowel disease. T cells acquire a gut-homing phenotype dependent on retinoic acid (RA) provided by intestinal dendritic cells (DC). We investigated whether liver antigen-presenting cells can induce gut tropism supporting an enterohepatic lymphocyte circulation. Priming of CD4+ T cells by liver sinusoidal endothelial cells (LSEC) supported migration into gut and gut-associated lymphoid tissue. As observed for T cells primed by intestinal DCs, this gut tropism depended on α4β7 integrin and CC chemokine receptor 9 (CCR9) expression by LSEC-primed CD4+ T cells. The induction of gut-homing molecules was mediated by RA, a derivate of vitamin A that is stored in large amounts within the liver. LSECs expressed functional retinal dehydrogenases and could convert vitamin A to RA. Conversely, the lack of signaling via the RA receptor prevented the expression of α4β7 integrin and CCR9 on LSEC-primed CD4+ T cells, consequently reducing their in vivo migration to the intestine. Other liver antigen-presenting cells failed to support high expression of α4β7 integrin on CD4+ T cells, thus, the potential to induce gut homing is restricted to LSECs. Conclusion: The capacity to promote gut tropism via vitamin A use is not unique for intestinal DCs but is also a feature of LSECs. Our data support the assumption that CD4+ T cells can migrate from the liver to the gut as one branch of a postulated enterohepatic lymphocyte circulation.

Background Given the chronic nature of psoriasis and the loss of response that can be observed with therapies over time, it is important to understand the long-;term efficacy of new treatments. Objective To evaluate maintenance of Week 16 responses with bimekizumab treatment through Year 3, in patients with moderate to severe plaque psoriasis. Methods Data were pooled from bimekizumab-treated patients in the 52-week (BE VIVID) and 56-week (BE READY and BE SURE) phase 3 studies, and their ongoing open-label extension (OLE), BE BRIGHT. Efficacy outcomes are reported through three years of bimekizumab treatment in patients with an efficacy response at Week 16. Missing data were imputed primarily using modified non-responder imputation (mNRI), with non-responder imputation and observed case data also reported. Results A total of 989 patients were randomized to bimekizumab at baseline in BE VIVID, BE READY, and BE SURE. At Week 16, 693 patients achieved ≥90% reduction from baseline in Psoriasis Area and Severity Index (PASI 90), 503 achieved 100% reduction from baseline in PASI (PASI 100), 694 achieved absolute PASI ≤2, and 597 achieved body surface area (BSA) ≤1%, and continued into the OLE. Of these, 93.0% maintained PASI 90, 80.8% maintained PASI 100, 94.0% maintained PASI ≤2, and 90.3% maintained BSA ≤1% responses through to three years of bimekizumab treatment (mNRI). Among Week 16 PASI 90 responders, 96.8% and 72.5% also achieved Investigator’s Global Assessment (IGA) 0/1 and PASI 100 at Week 16, respectively, and 92.2% and 73.4% achieved these responses at Year 3 (mNRI). Among Week 16 PASI 100 responders, 76.3% also achieved Dermatology Life Quality Index (DLQI) 0/1 at Week 16, and DLQI 0/1 response increased with continuous bimekizumab treatment to 89.0% at Year 3 (mNRI). Conclusions High levels of clinical response were maintained through to three years of bimekizumab treatment in the vast majority of Week 16 responders. Long-term treatment with bimekizumab was efficacious, with important benefits on health-related quality of life (HRQoL), in patients with moderate to severe plaque psoriasis.

The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor αβ was found in CD8 T cells, questioning the concept. We now demonstrate that αβ expression in murine CD4 memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced αβ. A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of αβ expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by αβ is imprinted in CD4 memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.