Differential expression of GPR15 on T cells during ulcerative colitis

Adamczyk, Alexandra; Gageik, Daniel; Frede, Annika; Pastille, Eva; Hansen, Wiebke; Rueffer, Andreas; Buer, Jan; Büning, Jürgen; Langhorst, Jost; Westendorf, Astrid M.

doi:10.1172/jci.insight.90585

Cited by 31 publications

(37 citation statements)

References 32 publications

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“…Some of these molecules like CXCR3, CCR5, CCR9, and GPR15 have been involved in gut homing, trafficking to, or retention in the intestine. [35][36][37][38] CCR5, which we found to be more present on circulating ST2 + versus ST2 − Tregs in intestinal cancer patients, has been implicated in the recruitment of Tregs to solid murine tumors, including CRC. 39 Moreover, there is evidence for a potential involvement of IL-33 in immune cell chemotaxis.…”

Section: Discussionmentioning

confidence: 74%

The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer

et al. 2019

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The composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3 + Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8 + T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3 + Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.

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Section: Discussionmentioning

confidence: 74%

The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer

et al. 2019

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“…GPR15 is expressed by subsets of memory, regulatory, and effector lymphocytes in human blood but not on naïve T cells ( 7 , 15 ). We analyzed the chemotactic effect of GPR15L on GPR15 + subsets of CD8 and CD4 effector/memory, Treg, CLA + skin-homing, and α4β7 + gut-homing T cells using an anti-GPR15 antibody.…”

Section: Resultsmentioning

confidence: 99%

A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15

et al. 2017

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Chemoattractants control lymphocyte recruitment from the blood, contributing to the systemic organization of the immune system. The G protein-linked receptor GPR15 mediates lymphocyte homing to the large intestines and skin. Here we show that the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived sushi containing domain-2 binding factor (CSBF), encoded by C10orf99 in the human and 2610528A11Rik in the mouse, functions as a chemokine ligand for GPR15 (GPR15L). GPR15L binds GPR15 and attracts GPR15-expressing T cells including lymphocytes in colon-draining lymph nodes and Vγ3+ thymic precursors of dermal epithelial T cells. Patterns of GPR15L expression by epithelial cells in adult mice and humans suggest a homeostatic role for the chemokine in lymphocyte localization to the large intestines, as well as a role in homing to the epidermis during wound healing or inflammation. GPR15L is also significantly expressed in squamous mucosa of the oral cavity and esophagus with still poorly defined regulation. Identification of the chemotactic activity of GPR15L adds to its reported antibacterial and tumor cell growth regulatory functions and suggests the potential of targeting GPR15L–GPR15 interactions for modulation of mucosal and cutaneous inflammation.

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“…In the current investigation, we chose to focus on an understudied systemic effect of smoking, i.e., its impact on levels of CD3+CD4+ helper T (T h ) cells expressing the G-protein-coupled receptor 15 (GPR15), a chemokine receptor encoded by the chromosome 3 gene GPR15. Originally identified as a coreceptor for simian immunodeficiency virus (SIV), human immunodeficiency virus 2 (HIV-2), and some human immunodeficiency virus 1 (HIV-1) strains [10][11][12], GPR15 has been linked to multiple smoking-associated diseases, including rheumatoid arthritis [13], inflammatory bowel disease [14][15][16], and multiple sclerosis [17], and psoriasis [18].…”

Section: Introductionmentioning

confidence: 99%

Cigarette and Cannabis Smoking Effects on GPR15+ Helper T Cell Levels in Peripheral Blood: Relationships with Epigenetic Biomarkers

Andersen

Lei

Beach

et al. 2020

Genes

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Background: Smoking causes widespread epigenetic changes that have been linked with an increased risk of smoking-associated diseases and elevated mortality. Of particular interest are changes in the level of T cells expressing G-protein-coupled receptor 15 (GPR15), a chemokine receptor linked with multiple autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and psoriasis. Accordingly, a better understanding of the mechanisms by which smoking influences variation in the GPR15+ helper T cell subpopulation is of potential interest. Methods: In the current study, we used flow cytometry and digital PCR assays to measure the GPR15+CD3+CD4+ populations in peripheral blood from a cohort of n = 62 primarily African American young adults (aged 27–35 years) with a high rate of tobacco and cannabis use. Results: We demonstrated that self-reported tobacco and cannabis smoking predict GPR15+CD3+CD4+ helper T cell levels using linear regression models. Further, we demonstrated that methylation of two candidate CpGs, cg19859270, located in GPR15, and cg05575921, located in the gene Aryl Hydrocarbon Receptor Repressor (AHRR), were both significant predictors of GPR15+CD3+CD4+ cell levels, mediating the relationship between smoking habits and increases in GPR15+CD3+CD4+ cells. As hypothesized, the interaction between cg05575921 and cg19859270 was also significant, indicating that low cg05575921 methylation was more strongly predictive of GPR15+CD3+CD4+ cell levels for those who also had lower cg19859270 methylation. Conclusions: Smoking leads changes in two CpGs, cg05575921 and cg19859270, that mediate 38.5% of the relationship between tobacco and cannabis smoking and increased GPR15+ Th levels in this sample. The impact of cg19859270 in amplifying the association between cg05575921 and increased GPR15+ Th levels is of potential theoretical interest given the possibility that it reflects a permissive interaction between different parts of the adaptive immune system.

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Differential expression of GPR15 on T cells during ulcerative colitis

Cited by 31 publications

References 32 publications

The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer

The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer

A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15

Cigarette and Cannabis Smoking Effects on GPR15+ Helper T Cell Levels in Peripheral Blood: Relationships with Epigenetic Biomarkers

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