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.
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.
Department of Pediatrics/Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Jeffrey B
JB
Brown
Paul
P
Cheresh
Zheng
Z
Zhang
Hyunji
H
Ryu
Elizabeth
E
Managlia
Terrence A
TA
Barrett
D000818:Animals; D002452:Cell Count; D002465:Cell Movement / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D016207:Cytokines; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D016264:Dextran Sulfate