title: Cytotoxic effector function of CD4-independent, CD8(+) T cells is mediated by TNF-α/TNFR.
abstract: BACKGROUND
  Liver parenchymal cell allografts initiate both CD4-dependent and CD4-independent, CD8(+) T cell-mediated acute rejection pathways. The magnitude of allospecific CD8(+) T cell in vivo cytotoxic effector function is maximal when primed in the presence of CD4(+) T cells. The current studies were conducted to determine if and how CD4(+) T cells might influence cytotoxic effector mechanisms.
  
  
  METHODS
  Mice were transplanted with allogeneic hepatocytes. In vivo cytotoxicity assays and various gene-deficient recipient mice and target cells were used to determine the development of Fas-, TNF-α-, and perforin-dependent cytotoxic effector mechanisms after transplantation.
  
  
  RESULTS
  CD8(+) T cells maturing in CD4-sufficient hepatocyte recipients develop multiple (Fas-, TNF-α-, and perforin-mediated) cytotoxic mechanisms. However, CD8(+) T cells, maturing in the absence of CD4(+) T cells, mediate cytotoxicity and transplant rejection that is exclusively TNF-α/TNFR-dependent. To determine the kinetics of CD4-mediated help, CD4(+) T cells were adoptively transferred into CD4-deficient mice at various times posttransplant. The maximal influence of CD4(+) T cells on the magnitude of CD8-mediated in vivo allocytotoxicityf occurs within 48 hours.
  
  
  CONCLUSIONS
  The implication of these studies is that interference of CD4(+) T cell function by disease or immunotherapy will have downstream consequences on both the magnitude of allocytotoxicity as well as the cytotoxic effector mechanisms used by allospecific CD8(+) cytolytic T cells.
authors.affiliation: Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210-1250, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Zimmerer
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Horne
authors.forename: Lori A
authors.initials: LA
authors.lastname: Fiessinger
authors.forename: Mason G
authors.initials: MG
authors.lastname: Fisher
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pham
authors.forename: Samiya L
authors.initials: SL
authors.lastname: Saklayen
authors.forename: Ginny L
authors.initials: GL
authors.lastname: Bumgardner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D016031:Liver Transplantation / Q000009:adverse effects / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; C491899:Fas protein, mouse; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C483886:perforin, mouse