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 utilized to determine the development of Fas-, TNF-α-, and perforin-dependent cytotoxic effectors mechanisms following 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 allocytotoxicity 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 employed by allospecific CD8+ cytolytic T cells.

Alloprimed CD8+ T Cells Regulate Alloantibody and Eliminate Alloprimed B Cells Through Perforin- and FasL-Dependent Mechanisms

“…These findings are consistent with the interpretation that alloprimed CD8 + T cells mediate cytotoxicity of alloprimed IgG1 + B cells through recognition of allopeptide presentation by MHC I. Since our prior studies demonstrate that the in vitro cytotoxicity assay preferentially reflects perforin-mediated cytotoxicity (17), we limit the interpretation of these results of allospecificity and MHC I/TCR cell-cell contact interactions to CD8 + T cell perforin-mediated cytotoxicity. In addition, we performed a similar side-by-side in vitro cytotoxicity assay for CD8 and B cell co-cultures using transwell membranes.…”

“…Despite alloantibody downregulation following bulk CD8 + T cell adoptive transfer to CD8 KO recipient mice, transplant survival was no different in CD8 KO recipients with or without adoptive transfer (day 14 for both). This is not surprising since bulk CD8 + T cells also reject hepatocytes (17,25–27). …”

“…However, in other studies, we also noted that perforin- or FasL-deficient transplant recipient mice produced increased amounts of alloantibody compared to wild-type controls (14). Alloprimed CD8 + T cells develop multiple cytotoxic effector mechanisms including FasL, perforin, and TNF-α (15–17). The current studies were conducted to test the hypothesis that CD8 + T cells might also downregulate alloantibody production through other mechanisms such as FasL-, perforin-, and/or TNF-α-mediated cytotoxic clearance of alloprimed IgG1 + B cells.…”

Preferential TNFα signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia

“…In addition to acting as a ligand to TNFRs, TNFα elicits outside-to-inside signals (reverse signaling) (15). In the liver, TNFα/TNFR signaling has been linked to several biological processes, including liver regeneration (16), regulation of CD8 + T cell cytotoxicity (17), and mechanisms of fulminant hepatitis (18) and fibrogenesis (19). Based on our previous report that TNFα Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis.…”

Roles of Aluminum Hydroxide and Monophosphoryl Lipid A Adjuvants in Overcoming CD4+ T Cell Deficiency To Induce Isotype-Switched IgG Antibody Responses and Protection by T-Dependent Influenza Vaccine

“…Another study demonstrated that both B7-1 (CD80) and B7-2 (CD86) costimulatory molecules on DCs were required for IgG1 and IgG2a responses (31). TNF-α pathway was important for activating cytotoxic effector CD8 + T cells in the absence of CD4 T cells (32). This study provides evidence that a CD4 genetic defect led to developing other compensatory immune components even in a mock (PBS) treatment condition.…”