Nat Immunol: GPR15 is a "homing" receptor for migration of T cells into the gut during the inflammatory response of the large intestine

January 20, 2015 / Bio-BIOON / -- T cell activation and differentiation occurs in each lymph node, so activated T cells need specific guidance to reach the interstitial function. Previous studies have demonstrated that T cell surface expresses a class of chemokine receptors that migrate to the vicinity of the tissue under the stimulation of the corresponding ligand and are stabilized by the interaction of T cell surfaces with adhesion molecules on the surface of epidermal cells. The intestine is a highly enriched area of ​​microorganisms and is therefore a highly "inflammatory" tissue. A large number of T lymphocytes are always present near the small intestine, but studies on the chemokines and ligands that direct these cells remain unclear.

GPR15 is an "orphan receptor" (ie, its ligand is unclear) and is also a helper receptor for HIV (immune-deficient virus). Its structure is very similar to known chemokine receptors. Recently, the Aida Habtezion team of the Stanford University School of Medicine published their research on the expression of GPR15 in mouse and human T lymphocytes and the migration of T cells into the large intestine during enteritis. .

The authors first used GPR15-GFP transgenic mice as subjects to analyze the expression of GPR15 in different tissue T cells. The results showed that the proportion of GPR15-GFP-positive T cells in the lamina propria of the large intestine was significantly higher than that in the small intestine and other peripheral lymphoid tissues. These positive cells were characteristic of effector cells or memory cells.

CD45RBhi CD4+ T cell transfer is a model of enteritis commonly used in immunology: transplantation of naïve T cells (ie, unactivated T cells) into mutant mice lacking T cells (RAG 2 knockout) due to the absence of Treg, T cells cause a serious autoimmune response. The authors transplanted na?ve T cells from wild-type and GPR 15 deletion mutant mice into RAG 2 deletion mutant mice. The results showed that the T cells of the GPR 15 deletion mutant mouse did not cause intestinal enteritis like the wild type. The most positive control, the combined transplantation of Tregs also inhibited the intestinal inflammatory response produced by wild-type mouse T cells.

The ability of GPR 15 deletion mutant T cells to lose enteritis has two explanations: 1. The production of effector T cells is affected; 2. The effector T cells can be produced normally, but their ability to migrate from the large intestine is affected. To confirm which specific reason, the authors mixed GFP+ GPR 15- with GFP+ GPR 15+ cells and transplanted them into RAG 2 deletion mutant mice, and analyzed the distribution of T cells before the onset of enteritis symptoms. The results showed that GFP+ GPR 15+ cells were more likely to accumulate in the large intestine than GFP+ GPR 15-cells; on the other hand, there was no significant difference in the ability of the two types of cells to differentiate into Th1 and Th17. The above results demonstrate that GPR15 mainly affects the migration of T cells to large intestine tissue.

Later, in order to study whether the results obtained from the mouse samples are equally applicable to humans, patients with ulcerative colitis (a type of Th2-type autoimmune disease), Crohn's disease (a typical type of Th1/Th17 autoimmune disease) Patients and normal samples were analyzed. The results showed that GPR15 expression in IL-5+, IL-13+ cell populations in patients with ulcerative colitis was much higher than in other samples (ie, related to Th2 cells); in addition, contrary to previous studies on mouse samples GPR15 was almost not expressed in Treg cells in human samples. Further analysis showed that GPR15-positive CD4+ T cells in humans expressed IL-4 (ie, Th2 type), while GPR15-positive CD4+ T cells in mice expressed IL-17 (ie, Th17 type). This result indicates that GPR15 has a marked difference in expression profiles between humans and mice.

Previous studies have been well understood: GATA-3 is a hallmark transcription factor for Th2 cell differentiation. Therefore, the authors wish to know whether a large amount of GPR15 expression in human Th2 cells is associated with GATA-3. By CHIP (chromosomal Immune precipitation: a technique for studying the interaction of transcription factors with DNA, often used in transcriptional regulation analysis). The method demonstrated that GATA-3 specifically binds to the GPR15 upstream enhancer region in human Th2 cells, whereas this phenomenon is absent in mouse Th2 cells. This finding explains why GPR15 is highly expressed in human Th2 cells. In addition, the authors also compared whether FoxP3 is involved in the regulation of GPR15 expression in human and mouse Treg cells. CHIP results show that FoxP3 interacts strongly with GPR15 upstream enhancer in human Treg cells, but in mice The medium interaction is weak. This finding suggests that FoxP3 specifically inhibits the expression of GPR15 in human Treg.

In summary, this study first proposed GPR15 as a "homing" receptor for the migration of effector T cells into the large intestine. Its expression in different cells of human and mouse led to the movement of different types of effector T cells to the large intestine. This effect has led to the emergence of different autoimmune diseases.