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

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 wild type and PSGL-1−/− mice received 2.5% 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 day 7 and 14. Recruitment of T-helper 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 (IFNγ, TNF) and Th17 (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.

PSGL-1: A New Player in the Immune Checkpoint Landscape

“…For example, Th1 and Th2 cells upregulate and express similar levels of PSGL-1 in vitro , but only Th1 cells can engage P-selectin [76]. Selplg −/− Th1 cells failed to infiltrate the colon in a DSS colitis model whereas Selplg −/− Th17 cells effectively migrated without PSGL-1 expression, indicating that T cell subsets can utilize posttranslational modifications on PSGL-1 to further fine tune effector T cell homing [78]. Furthermore, in sites of inflammation, the majority of CD4 + cells can exhibit selectin-binding capacity [79, 80].…”

The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

“…In this model, pharmacological depletion of platelets induces reduced rolling and adhesion of leukocytes [81]. Genetic depletion or pharmacological blockade of both P-selectin of PSGL-1 led to reduced platelet and leukocyte adhesion in mice, while findings concerning disease activity revealed contradictory results (see Table 3 and Table 4) [81,82,83,84,85,86]. Furthermore, the same group could show that genetic depletion of CD40 or its ligand is protective in animal model of colitis with reduced platelet and leukocyte adhesion (see Table 3).…”

Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway

“…In several animal models of UC and patients suffering from IBD, the accumulation and overexpression of Th1 and Th17 signature cytokines (IFN-γ and IL-17A, respectively) have been confirmed in the target tissues [9,10].…”