RESUMO
GPR15 is a chemoattractant receptor that facilitates colon homing of regulatory and effector CD4+ T cells in health and colitis. The molecular mechanisms that control GPR15 expression are not fully known. Here we report the presence of two highly conserved aryl hydrocarbon receptor (AHR) binding sequences in a 3' enhancer of GPR15, leading us to investigate AHR function in regulating GPR15 expression. Using luciferase reporter assays, we show that AHR activation increased GPR15 expression and requires both the AHR binding sites. Consistent with a transcriptional regulatory role, treatment with AHR agonists induce GPR15 expression on human CD4+ T cells. Using AHR-deficient mice, we demonstrate that the lack of AHR signaling drastically reduces GPR15 expression on effector/memory and Foxp3+ CD4+ T cells. In mixed bone marrow chimeras of AHR-deficient and wildtype cells, GPR15 expression was similarly diminished on AHR-deficient CD4+ effector/memory and regulatory T cells in the colon and small intestine. Furthermore, administration of AHR agonists upregulated GPR15 expression on CD4+ effector/memory T cells and increased their homing capability, especially to the colon. Collectively, our studies reveal a novel function of the AHR in regulation of GPR15 expression and increased colon trafficking of CD4+ T cells expressing GPR15.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Regulação da Expressão Gênica , Receptores de Hidrocarboneto Arílico , Receptores Acoplados a Proteínas G , Receptores de Peptídeos , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Fatores de Transcrição Forkhead , Fator de Transcrição GATA3/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , CamundongosRESUMO
BACKGROUND: Allografts donated after cardiac death (DCD) are the fastest growing organ source worldwide. Unfortunately, information is lacking on how to judge these organs' viability. Here, we analyzed the effects of donor characteristics, including age and BMI, on outcomes of DCD simultaneous-pancreas-kidney transplantation (SPK). METHODS: We evaluated UNOS DCD-SPK transplants from 1988 to 2012. Effects of donor characteristics on graft and recipient survival were evaluated using Cox Regression and the Kaplan-Meier method, and compared to predictions from the pancreas and kidney donor risk indices (PDRI, KDRI). RESULTS: Compared to grafts≤40(nâ¯=â¯38), grafts>40(nâ¯=â¯189) had lower 1-year (73.4%⯱â¯7.2% vs 88.2%⯱â¯2.4%) and 10-year (50.3%⯱â¯10% vs 66.3%⯱â¯6.9%) pancreas survival, and twice the rate of kidney failure (HR2.1, 95%CI 1.15-3.83, pâ¯<â¯0.05) and pancreas failure (HR2.07, 95%CI 1.16-3.70, pâ¯<â¯0.05). BMI correlated with pancreas failure and recipient mortality. CONCLUSIONS: Donor age and BMI are significant predictors of DCD-SPK outcomes. Graft age appears to be as good a predictor of outcome as PDRI and KDRI.