P-Selectin Glycoprotein Ligand-1 Is Needed for Sequential Recruitment of T-Helper 1 (Th1) and Local Generation of Th17 T Cells in Dextran Sodium Sulfate (DSS) Colitis


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Abstract

Background:Activated effector T cells contribute to tissue injury observed in inflammatory bowel disease. T cells are recruited to effector sites after activation in peripheral lymph nodes directs expression of tissue-specific homing receptors. One such mechanism for effector T cell recruitment employs activation-induced fucosylation of P-selectin glycoprotein ligand (PSGL)-1 that mediates binding to endothelial P-selectin. Here we examine the differential role of PSGL-1 in recruiting effector T-cell subsets in colitis.Methods:C57BL/6 wildtype and PSGL-1−/− mice received 2.5% dextran sodium sulfate (DSS) for 6 days and were euthanized 7 and 14 days after the initiation of DSS. Disease activity was monitored throughout. Histologic colitis scores, colonic CD4+ accumulation, and cytokine production were assessed at days 7 and 14. Recruitment of T-helper (Th) subsets was assessed by enumerating adoptively transferred Th1 or Th17 CD4+ cells 2 days after transfer to DSS-treated mice.Results:DSS colitis increases CD4+ T cells in colonic tissue and induces Th1 (interferon gamma [IFN-γ], tumor necrosis factor [TNF]) and Th17 (interleukin [IL]-17, IL-22) cytokines. Loss of PSGL-1 attenuates DSS colitis, decreases colonic CD4+ T cell numbers, and reduces both Th1 and Th17 cytokine production. Colitis increases recruitment of Th1 (19-fold) and Th17 (2.5-fold) cells. PSGL-1 deficiency in transferred T cells abrogates colonic recruitment of Th1 cells in DSS colitis, whereas Th17 recruitment is unaffected.Conclusions:PSGL-1 selectively controls Th1 recruitment in colitis. Whereas Th17 recruitment is independent of PSGL-1, generation of colonic Th17 cytokine requires initial Th1 recruitment. Therefore, attenuating PSGL-1 binding may prevent colonic recruitment of disease-causing Th1 cells that promote local Th17 generation. (Inflamm Bowel Dis 2011;)

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