Abstract
Memory CD8 T cells can be activated and induced to produce cytokines and increase stores of cytolytic proteins not only in response to cognate antigen (Ag) but also in response to inflammatory cytokines (bystander responses). Importantly, bystander memory CD8 T cell functions have been shown to be dependent upon memory CD8 T cell fitness, since exhausted CD8 T cells have diminished capacity to respond to inflammatory cues. While it is known that memory CD8 T cell functional abilities, including ability to produce cytokines in response to cognate Ag, change with time after initial Ag encounter and upon multiple Ag stimulations (e.g., primary vs. tertiary CD8 T cell responses), it is unknown if bystander memory CD8 T cell responses are influenced by time or by Ag-exposure history. Here, we examined time and Ag-stimulation history-dependent alterations in virus-specific memory CD8 T cell bystander functions in response to inflammatory cytokines and unrelated bacterial infection. We found that expression of cytokine receptors and ability to produce IFN-γ following heterologous infection or incubation with inflammatory cytokines decreases with time following initial Ag encounter and increases with additional Ag encounters, suggesting that the ability to sense inflammation and respond with bystander cytokine production is dependent on age and Ag-stimulation history of memory CD8 T cells. These data shed further light on the regulation of memory CD8 T cell effector functions and have important implications for the development of vaccines designed to elicit protective memory CD8 T cells.
Highlights
CD8 T cell effector functions, including cytokine secretion and targeted delivery of cytolytic molecules to infected target cells, are critical for the clearance of invading intracellular bacterial, viral, and parasitic infections [1]
We began by using a well-established in vivo model to elicit bystander memory CD8 T cell responses in the absence of cognate Ag, adoptively transferring naïve TCR-transgenic P14 cells specific for GP33 LCMV-derived epitope into recipient mice followed by LCMV-Arm infection, and at a memory time point infecting mice with Listeria monocytogenes (LM), which does not express Ag recognized by the memory P14 cells
Bystander memory CD8 T cell responses were dependent upon the dose of LM used, as a stepwise increase in the percentage of P14 cells producing IFN-γ was observed upon infection with 1 × 104, 1 × 105, and 1 × 106 colony forming units (CFU) of LM (Figure S1A in Supplementary Material)
Summary
CD8 T cell effector functions, including cytokine secretion and targeted delivery of cytolytic molecules to infected target cells, are critical for the clearance of invading intracellular bacterial, viral, and parasitic infections [1]. CD8 T cell activation leading to the release of cytokines and delivery of cytolytic molecules is most often thought of as being driven by cognate Ag recognition, and work describing time and Ag-stimulation history-dependent changes in CD8 T cell cytokine-producing abilities have examined Ag-dependent CD8 T cell activation. Memory CD8 T cell activation leading to IFN-γ production and increased stores of cytolytic molecules has been shown to be driven in an Ag-independent manner [13]. At present it is unknown if Ag-independent activation, otherwise known as bystander responses, of memory CD8 T cells are dependent upon time after initial Ag encounter or Ag-stimulation history
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