Recruitment of IFN-γ-Producing (Th1-Like) Cells into the Inflamed Retina In Vivo Is Preferentially Regulated by P-Selectin Glycoprotein Ligand 1:P/E-Selectin Interactions

Abstract

Although there is evidence that altering the Th1/Th2 balance toward Th2 cells may be important in the resolution of Th1-type autoimmune disease, adoptive transfer of Th2 cells is not effective in protecting against Th1-type disease and may cause disease. Therefore, we examined the recruitment of Th1- and Th2-like cells into the retina in the murine autoimmune disease experimental autoimmune uveoretinitis. CD4 T cells were polarized in vitro to IFN-γ-producing Th1-like cells and non-IFN-γ-producing Th2-like cells, labeled, and adoptively transferred. Trafficking to the retina in vivo was evaluated by scanning laser ophthalmoscopy and infiltration by confocal microscopy. There were more rolling and adherent Th1-like cells and they rolled more slowly than did Th2-like cells. Th1-like cells were preferentially recruited into the retinal parenchyma at both initiation and resolution. Surface P-selectin glycoprotein ligand 1 (PSGL-1) and LFA-1 were up-regulated on both populations but were expressed at higher levels on Th1-like cells. Up-regulation of CD44 expression was higher on Th2-like cells. P-selectin, E-selectin, and ICAM-1 are up-regulated on postcapillary venules in the retina. Pretreatment of Th1-like cells with anti-PSGL-1 inhibited rolling and infiltration of Th1-like cells but not Th2-like cells, providing direct in vivo evidence for the inability of Th2 to respond to P/E-selectin despite increased expression of PSGL-1. Anti-LFA-1 pretreatment inhibited infiltration of both Th1- and Th2-like cells, but more so Th-1. We suggest that random trafficking of activated T cells (both Th1 and Th2) across the blood-retina barrier is mediated by CD44:CD44R and LFA-1:ICAM-1, whereas preferential recruitment of Th1 cells is mediated by PSGL-1:P/E-selectin.

Privilege revisited: an evaluation of the eye's defence mechanisms

“…[46][47][48] However, even here it is selective because only certain subtypes of T cell, such as interferon gamma producing Th1 cells, readily cross the retinal vessels. 49 In addition, even when cells cross the vessels, they require to be activated systemically and to circulate for some time before they cross the vessels into the retina. 50 This applies to both T cells and monocytes and suggests that penetration of the barrier in inflammation requires the vessel wall to be 'made ready' for transendothelial migration, probably by weakening of the TJs.…”

Bowman lecture on the role of inflammation in degenerative disease of the eye

“…As indicated above, Th1 cells appear to be selectively recruited into the retina in this process. 20 These observations have clear significance for uveitis pathogenesis in humans. Assuming a similar process in autoimmune/immune-mediated IOI, extraocularly activated T cells likely circulate in the system for a variable period of time (weeks) before they breach the retinal barrier, implying that uveitis is a systemic disease initiated outside the eye.…”

E- and P-Selectins Synergistically Inhibit Bleomycin-Induced Pulmonary Fibrosis

“…Furthermore, in E-selectin Ϫ/Ϫ mice treated with anti-P-selectin mAb, depletion of NK1.1 ϩ cells did not further augment the severity of lung fibrosis (Figure 7), suggesting that defective recruitment of NKT cells plays a major role in exacerbating lung fibrosis by the blockade of E-and P-selectins. Because it has been shown that P-and E-selectins preferentially mediate rolling and emigration of Th1 cells over Th2 cells, 36,37 E-and P-selectins may mediate the recruitment of NKT cells into the lung. In this study, CD3…”