Cytotoxic effector function of CD4-independent, CD8(+) T cells is mediated by TNF-α/TNFR

Transplantation. 2012 Dec 15;94(11):1103-10. doi: 10.1097/TP.0b013e318270f3c0.


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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4 Antigens / genetics
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cytotoxicity, Immunologic*
  • Graft Rejection / immunology*
  • Graft Survival
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatocytes / transplantation*
  • Liver Transplantation / adverse effects
  • Liver Transplantation / immunology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Pore Forming Cytotoxic Proteins / deficiency
  • Pore Forming Cytotoxic Proteins / genetics
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type II / deficiency
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Signal Transduction
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism*
  • fas Receptor / genetics
  • fas Receptor / metabolism


  • CD4 Antigens
  • Fas protein, mouse
  • Pore Forming Cytotoxic Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • perforin, mouse