CD8+ T Cell-Dependent Elimination of Dendritic Cells In Vivo Limits the Induction of Antitumor Immunity

Abstract

The fate of dendritic cells (DC) after they have initiated a T cell immune response is still undefined. We have monitored the migration of DC labeled with a fluorescent tracer and injected s.c. into naive mice or into mice with an ongoing immune response. DC not loaded with Ag were detected in the draining lymph node in excess of 7 days after injection with maximum numbers detectable ∼40 h after transfer. In contrast, DC that had been loaded with an MHC class I-binding peptide disappeared from the lymph node with kinetics that parallel the known kinetics of activation of CD8+ T cells to effector function. In the presence of high numbers of specific CTL precursors, as in TCR transgenic mice, DC numbers were significantly decreased by 72 h after injection. The rate of DC disappearance was extremely rapid and efficient in recently immunized mice and was slower in “memory” mice in which memory CD8+ cells needed to reacquire effector function before mediating DC elimination. We also show that CTL-mediated clearance of Ag-loaded DC has a notable effect on immune responses in vivo. Ag-specific CD8+ T cells failed to divide in response to Ag presented on a DC if the DC were targets of a pre-existing CTL response. The induction of antitumor immunity by tumor Ag-loaded DC was also impaired. Therefore, CTL-mediated clearance of Ag-loaded DC may serve as a negative feedback mechanism to limit the activity of DC within the lymph node.

Depletion of CD8+ T Cells Exacerbates CD4+ Th Cell-Associated Inflammatory Lesions During Murine Mycoplasma Respiratory Disease

“…Alternatively, CD8 ϩ T cells have been shown to act as veto cells in peripheral tolerance against graft rejection through TGF-␤1 production (64,65), and it is possible that a similar mechanism is involved in the modulation of mycoplasma respiratory disease. An additional mechanism may be through the reduction of APC numbers due to CD8 ϩ T cell-mediated cytolysis (66), thereby indirectly decreasing Th cell activation. Interestingly, the expansion of CD8 ϩ T cells is not found in all inflammatory responses in the lung, as nasal immunization using cholera toxin results in a perivascular and peribronchial mononuclear cell infiltrate that is comprised of CD4 ϩ T cells, but not CD8 ϩ T cells (49).…”

Ex vivo generation of genetically modified dendritic cells for immunotherapy: implications of lymphocyte contamination

“…Both CD4 + and CD8 + T-cell-mediated killing of cognate APC populations including DCs, B cells, and macrophages has been reported in several studies [20][21][22][23][43][44][45] and was shown to be mediated via Fas ligand (FasL)-dependent 20,[46][47][48] or -independent mechanisms. 23,44 Similarly, CD8 + CTL-mediated elimination of transplanted neo-antigen-positive T cells and other hematopoietic cells has been previously demonstrated in vivo both in animal models [27][28][29] and humans.…”

“…[17][18][19] Recently, it has been documented that DCs undergo rapid apoptosis during antigen-specific interaction with T cells both in vitro 20 and in vivo. [21][22][23][24] Several studies have shown that genetically modified DCs expressing TAA could effectively process and present antigenic peptides to T cells and trigger cytotoxic response against tumor cells expressing the target antigen. 12,25 It is important to consider that the TAA-modified DCs would also become a potential target and are at risk of being eliminated by the effector T cells they have activated.…”

Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency

“…As T-cell priming is drastically affected by the expression levels of costimulatory molecules on DCs, many DC-based vaccine strategies are focused on manipulating the DC activation state. Activated antigen-bearing DCs are unexpectedly short lived in draining LNs, 5 however, and phagocytosis or reprocessing of antigens from dead DCs to immature antigen-presenting cells may lead to tolerance. 6 Thus, the lifespan of DCs in vivo is a critical factor for the regulation of antitumor immunity, and the short lifespan of DC vaccines limits the efficiency of DC-based cancer immunotherapy.…”