Apoptosis by neglect of CD4+ Th cells in granulomas: a novel effector mechanism involved in the control of egg-induced immunopathology in murine schistosomiasis.
In infection with Schistosoma mansoni, parasite eggs precipitate an intrahepatic granulomatous and fibrosing inflammation that is mediated by CD4(+) Th cells. Compared with CBA mice, C57BL/6 mice develop smaller granulomas composed of cells that exhibit reduced proliferative responses to schistosome egg Ags. In the present study, we investigated CD4(+) T cell apoptosis as a possible mechanism that could account for this subdued response. We found throughout the course of several infection weeks a markedly higher proportion of apoptotic CD4(+) T cells in granulomas from C57BL/6 mice than in those from CBA mice ex vivo; the apoptosis further increased upon cell cultivation in vitro. Activation-induced cell death or CD8(+) T cells failed to account for the enhanced apoptosis as infected Fas-, Fas ligand,- and CD8-deficient mice exhibited similar apoptosis to that seen in wild-type counterparts. However, a strikingly lower IL-2 production by schistosome egg Ag-stimulated C57BL/6 granuloma and mesenteric lymph node cells suggested the possibility of apoptosis due to growth factor deprivation. Indeed, the CD4(+) T cell apoptosis was significantly reversed by addition of rIL-2 in vitro, or by injection of rIL-2 in vivo, which also resulted in significant exacerbation of granulomatous inflammation. These findings indicate that apoptosis by neglect can represent a significant means of controlling CD4(+) T cells that mediate the immunopathology in schistosomiasis.
Rutitzky
Laura I
LI
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Mirkin
Gerardo A
GA
Stadecker
Miguel J
MJ
D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D006099:Granuloma / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology; D008643:Mesentery; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D019463:Mice, Inbred MRL lpr; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
D000947:Antigens, Helminth; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D019014:fas Receptor