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.
Bibliographical noteFunding Information:
The authors wish to thank Stacey Hartwig and Christina Winborn for help with maintenance of mouse colonies and preparation of reagents used in this study Research reported in this publication was supported by the National Center for Research Resources of the National Institutes of Health under Award Number 1S10OD16199-01A1 and the the National Institutes of Health Grants: GM113961, AI114543 (VB), AI119160 (VB and H-HX), and 4T32AI007260-30 (MM).
© 2017 Martin, Shan, Xue and Badovinac.
Copyright 2017 Elsevier B.V., All rights reserved.
- Antigen-exposure history
- Bystander responses
- CD8 T cells
- Time-dependent functions