Abstract
Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity.
Highlights
Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice
We and others have shown that VM cells arise in the periphery6 in a PLZF/IL-4/natural killer T (NKT) cell-independent, but interleukin (IL)-15-dependent, manner7, once developed they can respond vigorously to cytokines such as IL-4 and type I interferon (IFN)9, and that they accumulate in the aged host10
Other than the fact that these cells arise in the periphery and are dependent on IL-15, little else was known about VM development
Summary
Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Recent data examining the gene expression profile of CD5hi and CD5lo naive T cells suggests that CD5hi cells are transcriptionally poised to engage both proliferative and effector functions far more rapidly than CD5lo cells of the same specificity14 While these studies are informative as to the naive T-cell response to antigen in an inflammatory setting, the cues by which a naive phenotype T cell within the periphery integrates tonic and cytokine signals in a non-lymphopenic environment to become a member of the VM pool are still poorly defined. In the absence of IL-15, VM expression of granzyme B and NKG2D was nearly ablated, as was their capacity to mediate bystander protection These data give a new functional role for VM cells during exposure to pathogens independent of antigen specificity as well as a new role for IL-15 during the primary response. We show that a previously identified VM-like subset in humans traffics extensively to the liver, accumulates with age and collectively displays the phenotypic and functional traits identified in the mouse
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