Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Abstract

ObjectiveGut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in IBDs. We aimed to analyse the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and G protein receptor GPR15.DesignWe assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanised mouse model in dextran sodium sulfate-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice.ResultsExpression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with UC as compared with Crohn’s disease and controls. In vivo analysis in a humanised mouse model showed augmented gut homing of UC Treg cells as compared with controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood.Conclusionsα4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff cell homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic Teff cell expansion.

Differential expression of GPR15 on T cells during ulcerative colitis

“…This raises the question of whether GPR15 is not involved in the migration of Tregs into the inflamed colon, a concept favored by Fischer and colleagues. They showed in a humanized mouse model that α4β7 integrin is important for homing of UC Tregs into the colon (18). Interestingly, we detected only a very small population of Tregs that coexpress α4β7 and GRP15 in PBMCs of healthy individuals and UC patients, providing evidence that there might be differences in function and migration among α4β7 + Tregs, GRP15 + Tregs, and α4β7 + GRP15 + Tregs.…”

“…Additionally, they imply that the expression of GPR15 might be downregulated after binding to the potential ligand or within the inflamed environment or that GPR15 is not an exclusive master regulator for the migration of Tregs into the inflamed colon. A former study in a humanized mouse model by Fischer and colleagues (18) suggested that α4β7 integrin is crucial for homing of Tregs from UC patients into the colon. Well in line with their results, we detected an increased expression of α4β7 integrin on Tregs from peripheral blood mononuclear cells (PBMCs) of UC patients ( Figure 5A), similar to our results obtained for GPR15 expression ( Figure 2B).…”

“…The gut microbiota and its metabolites play an important role in the onset and perturbation of intestinal inflammation (2). Interestingly, short-chain fatty acids (SCFA), such as butyric acid and propionic acid, were shown to modulate T cell differentiation and the expression of GPR15, respectively, and could therefore be involved in dampening intestinal inflammation (12,18,19). To gain further insights into whether the downregulation of GPR15 on Tregs could be due to an alteration in the microbiota and its metabolites, we measured the SCFA in fecal samples of UC patients in remission (baseline) and active disease.…”

Current and emerging therapeutic targets for IBD

“…These infections were prob ably related to natalizumab induced blockade of T cell homing to the brain via α4β1 integrins, suggesting that a more specific blockade of α4β7 integrins was important. Subsequently, the α4β7 integrin specific antibody vedolizumab was developed and showed efficacy in clinical phase III trials for remission induction and maintenance in Crohn's disease and ulcerative colitis [58][59][60][61][62][63] .…”

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

“…Intravital confocal microscopy analyses upon adoptive transfer of T cells were performed according to a previously published study (53 RPMI 1640 medium (10% FCS, 1% penicillin-streptomycin, 1% nonessential amino acids, 1% L-glutamine, and 0.1 % β-mercaptoethanol) and activated with 10 μg/ml plate-bound anti-CD3 (clone 145-2C11; BioXcell) and 1 μg/ml soluble anti-CD28 (clone 37.51; BioXcell) antibodies. T cell cultures were additionally supplemented with 10 μg/ml soluble anti-IFN-γ (clone XMG1.2; BioXcell) antibody, either alone or together with 2 ng/ml recombinant IL-7 (rIL-7) (R&D Systems).…”