Th1 and Th2 effector CD4+ T cells orchestrate distinct counterregulatory biological responses. To deliver effective tissue Th1- and Th2-type responses, Th1 and Th2 cell recruitment into tissue must be differentially regulated. We show that tissue-derived STAT1 controls the trafficking of adoptively transferred, Ag-specific, wild-type Th1 cells into the lung. Trafficking of Th1 and Th2 cells is differentially regulated as STAT6, which regulates Th2 cell trafficking, had no effect on the trafficking of Th1 cells and STAT1 deficiency did not alter Th2 cell trafficking. We demonstrate that STAT1 control of Th1 cell trafficking is not mediated through T-bet. STAT1 controls the recruitment of Th1 cells through the induction of CXCL9, CXCL10, CXCL11, and CXCL16, whose expression levels in the lung were markedly decreased in STAT1-/- mice. CXCL10 replacement partially restored Th1 cell trafficking in STAT1-deficient mice in vivo, and deficiency in CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, impaired the trafficking of adoptively transferred Th1 cells in wild-type mice. Our work identifies that STAT1 in peripheral tissue regulates the homing of Ag-specific Th1 cells through the induction of a distinct subset of chemokines and establishes that Th1 and Th2 cell trafficking is differentially controlled in vivo by STAT1 and STAT6, respectively.

Th1 and Th2 effector CD4+ T cells orchestrate distinct counterregulatory biological responses. To deliver effective tissue Th1- and Th2-type responses, Th1 and Th2 cell recruitment into tissue must be differentially regulated. We show that tissue-derived STAT1 controls the trafficking of adoptively transferred, Ag-specific, wild-type Th1 cells into the lung. Trafficking of Th1 and Th2 cells is differentially regulated as STAT6, which regulates Th2 cell trafficking, had no effect on the trafficking of Th1 cells and STAT1 deficiency did not alter Th2 cell trafficking. We demonstrate that STAT1 control of Th1 cell trafficking is not mediated through T-bet. STAT1 controls the recruitment of Th1cells through the induction of CXCL9, CXCL10, CXCL11, and CXCL16, whose expression levels in the lung were markedly decreased in STAT1−/− mice. CXCL10 replacement partially restored Th1 cell trafficking in STAT1-deficient mice in vivo, and deficiency in CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, impaired the trafficking of adoptively transferred Th1 cells in wild-type mice. Our work identifies that STAT1 in peripheral tissue regulates the homing of Ag-specific Th1 cells through the induction of a distinct subset of chemokines and establishes that Th1 and Th2 cell trafficking is differentially controlled in vivo by STAT1 and STAT6, respectively.

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)