Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages.
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 (Mphi) via an IL-4-, IL-13-, IL-10-, TGF-beta-, and NO-independent, but cell contact-dependent, mechanism. F4/80(+) Mphi isolated from worm-infected mice were shown to induce anergy of naive T cells in vitro. Furthermore, naive Mphi exposed to live worms in vitro also induced anergy in naive T cells. Flow cytometry on in vivo and in vitro worm-modulated Mphi 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 Mphi 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.
Smith
Philip
P
Department of Biochemistry, Trinity College, Dublin, Ireland.
Walsh
Caitriona M
CM
Mangan
Niamh E
NE
Fallon
Rosie E
RE
Sayers
Jon R
JR
McKenzie
Andrew N J
AN
Fallon
Padraic G
PG
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D012550:Schistosoma mansoni / Q000276:immunology / Q000378:metabolism*; D012555:Schistosomiasis mansoni / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D010455:Peptides; C036763:monocyte-macrophage differentiation antigen; D009569:Nitric Oxide