CD8α+ Dendritic Cell <i>Trans</i> Presentation of IL-15 to Naive CD8+ T Cells Produces Antigen-Inexperienced T Cells in the Periphery with Memory Phenotype and Function

TLDR

Memory‑phenotype CD8⁺ T cells, identified over the past two decades, exhibit higher effector functions than naive CD8⁺ T cells. The study investigates whether IL‑15 trans‑presentation by peripheral CD8α⁺ dendritic cells generates virtual memory CD8⁺ T cells independent of innate memory subsets. The authors isolated antigen‑specific cells from unprimed mice and identified a novel subset that, while naïve to antigen, displays memory‑like phenotype and function due to homeostatic proliferation. Loss of IL‑15, CD122/eomesodermin, or CD8α⁺ dendritic cells abolishes VM cells, while IL‑15‑driven homeostatic expansion in non‑lymphopenic hosts generates antigen‑inexperienced memory CD8⁺ T cells that can mount rapid vaccine responses.

Abstract

Various populations of memory phenotype CD8(+) T cells have been described over the last 15-20 y, all of which possess elevated effector functions relative to naive phenotype cells. Using a technique for isolating Ag-specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal Ag, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation. We show in this study that these virtual memory (VM) cells are independent of previously identified innate memory cells, arising as a result of their response to IL-15 trans presentation by lymphoid tissue-resident CD8α(+) dendritic cells in the periphery. The absence of IL-15, CD8(+) T cell expression of either CD122 or eomesodermin or of CD8a(+) dendritic cells all lead to the loss of VM cells in the host. Our results show that CD8(+) T cell homeostatic expansion is an active process within the nonlymphopenic environment, is mediated by IL-15, and produces Ag-inexperienced memory cells that retain the capacity to respond to nominal Ag with memory-like function. Preferential engagement of these VM T cells into a vaccine response could dramatically enhance the rate by which immune protection develops.