CD8 T cells comprising the memory pool display considerable heterogeneity, with individual cells differing in phenotype and function. This review will focus on our current understanding of heterogeneity within the antigen-specific memory CD8 T cell compartment and classifications of memory CD8 T cell subsets with defined and discrete functionalities. Recent data suggest that phenotype and/or function of numerically stable circulatory memory CD8 T cells are defined by the age of memory CD8 T cell (or time after initial antigen-encounter). In addition, history of antigen stimulations has a profound effect on memory CD8 T cell populations, suggesting that repeated infections (or vaccination) have the capacity to further shape the memory CD8 T cell pool. Finally, genetic background of hosts and history of exposure to diverse microorganisms likely contribute to the observed heterogeneity in the memory CD8 T cell compartment. Extending our tool box and exploring alternative mouse models (i.e., “dirty” and/or outbred mice) to encompass and better model diversity observed in humans will remain an important goal for the near future that will likely shed new light into the mechanisms that govern biology of memory CD8 T cells.

No abstract

Activated CD8+ T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained remains less understood. Here we show Runx3 deficiency limits clonal expansion and impairs upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8+ TEFF cells aberrantly upregulate genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ complex deploys H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program. Ablating Tcf7 in Runx3-deficient CD8+ TEFF cells prevents the upregulation of TFH genes and ameliorates their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforces acquisition of cytotoxic functions and protects the cytotoxic lineage integrity by preventing TFH-lineage deviation.

Mortality from sepsis frequently results from secondary infections, and the extent to which sepsis affects pathogen-specific memory CD8 T cell responses remains unknown. Using the cecal-ligation and puncture (CLP) model of polymicrobial sepsis, we observed rapid apoptosis of pre-existing memory CD8 T cells after sepsis induction that led to a loss in CD8 T cell-mediated protection. Ag-sensitivity (functional avidity) and Ag-driven secondary expansion of memory CD8 T cells were decreased after sepsis, further contributing to the observed loss in CD8 T cell-mediated immunity. Moreover, Ag-independent bystander activation of memory CD8 T cells in response to heterologous infection was also significantly impaired early after sepsis induction. The reduced sensitivity of pre-existing memory CD8 T cells to sense inflammation and respond to heterologous infection by IFN-γ production was observed in inbred and outbred hosts and controlled by extrinsic (but not cell intrinsic) factors suggesting that sepsis-induced changes in the environment regulates innate functions of memory CD8 T cells. Taken together, the data in this study revealed a previously unappreciated role of sepsis in shaping the quantity and functionality of infection- or vaccine-induced memory CD8 T cells and will help further define the decline in T cell-mediated immunity during the sepsis-induced phase of immunosuppression.

The extent to which the progeny of one primary memory CD8 T cell differs from the progeny of one naïve CD8 T cell of the same specificity remains an unresolved question. In order to explore cell autonomous functional differences between naïve and memory CD8 T cells that are not influenced by differences in the priming environment, an experimental model has been developed in which physiological numbers of both populations of cells were co-transferred into naïve hosts before antigen-stimulation. Interestingly, naïve CD8 T cells undergo greater expansion in numbers than primary memory CD8 T cells after various infections or immunizations. The intrinsic ability of one naïve CD8 T cell to give rise to more effector CD8 T cells than one memory CD8 T cell is independent of the number and quality of primary memory CD8 T cells present in vivo. The sustained proliferation of newly activated naïve CD8 T cells contributed to their greater magnitude of expansion. In addition, longitudinal analyses of primary and secondary CD8 T cell esponses revealed that on a per cell basis naïve CD8 T cells generate higher numbers of long-lived memory cells than primary memory CD8 T cells. This enhanced ‘memory generation potential’ of responding naïve CD8 T cells occurred despite the delayed contraction of secondary CD8 T cell responses. Taken together, the data presented here revealed previously unappreciated differences between naïve and memory CD8 T cells and will help further define the functional potential for both cell types.