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The Journal of Immunology, 2004, 173: 1240-1248.
Copyright © 2004 by The American Association of Immunologists

Schistosoma mansoni Worms Induce Anergy of T Cells via Selective Up-Regulation of Programmed Death Ligand 1 on Macrophages1

Philip Smith*, Caitriona M. Walsh*, Niamh E. Mangan*, Rosie E. Fallon*, Jon R. Sayers{dagger}, Andrew N. J. McKenzie{ddagger} and Padraic G. Fallon2,*

* Department of Biochemistry, Trinity College, Dublin, Ireland; {dagger} Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, United Kingdom; and {ddagger} Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom

Infectious pathogens can selectively stimulate activation or suppression of T cells to facilitate their survival within humans. In this study we demonstrate that the trematode parasite Schistosoma mansoni has evolved with two distinct mechanisms to suppress T cell activation. During the initial 4- to 12-wk acute stages of a worm infection both CD4+ and CD8+ T cells are anergized. In contrast, infection with male and female worms induced T cell anergy at 4 wk, which was replaced after egg laying by T cell suppression via a known NO-dependent mechanism, that was detected for up to 40 wk after infection. Worm-induced anergy was mediated by splenic F4/80+ macrophages (M{phi}) via an IL-4-, IL-13-, IL-10-, TGF-{beta}-, and NO-independent, but cell contact-dependent, mechanism. F4/80+ M{phi} isolated from worm-infected mice were shown to induce anergy of naive T cells in vitro. Furthermore, naive M{phi} exposed to live worms in vitro also induced anergy in naive T cells. Flow cytometry on in vivo and in vitro worm-modulated M{phi} revealed that of the family of B7 costimulatory molecules, only programmed death ligand 1 (PD-L1) was selectively up-regulated. The addition of inhibitory mAb against PD-L1, but not PD-L2, to worm-modulated M{phi} completely blocked the ability of these cells to anergize T cells. These data highlight a novel mechanism through which S. mansoni worms have usurped the natural function of PD-L1 to reduce T cell activation during early acute stages of infection before the subsequent emergence of egg-induced T cell suppression in the chronic stages of infection.




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