CD8α+ Dendritic CellTransPresentation of IL-15 to Naive CD8+ T Cells Produces Antigen-Inexperienced T Cells in the Periphery with Memory Phenotype and Function

Abstract

Various populations of memory phenotype CD8+ T cells have been described over the last 15–20 years, all of which possess elevated effector functions relative to naïve phenotype cells. Using a technique for isolating antigen specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal antigen, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation (HP). We show here that these “Virtual Memory” 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+ DCs in the periphery. The absence of IL-15, CD8+ T cell expression of either CD122 or Eomes, or of CD8a+ DCs all lead to the loss of Virtual Memory cells in the host. Our results show that CD8+ T cell homeostatic expansion is an active process within the non-lymphopenic environment, is mediated by IL-15, and produces antigen inexperienced memory cells which retain the capacity to respond to nominal antigen with memory-like function. Preferential engagement of these “Virtual Memory” T cells into a vaccine response could dramatically enhance the rate by which immune protection develops.

Virtual memory CD8 T cells display unique functional properties

“…Furthermore, Vβ5 VM cells displayed low levels of α4 integrin (CD49d) compared with antigen primed TM cells (Fig. S1 C and D), in keeping with previous studies on phenotypic differences between polyclonal VM and TM populations (11,16). Hence, the phenotype of naïve and VM CD8 T cells within the Ova/K b -specific population of Vβ5 mice resembled that of normal mice, yet the elevated frequency of OVA-specific cells in Vβ5 mice provided an opportunity to compare the antigen-specific responses by naïve, VM, and TM subsets.…”

“…This raised the question of whether VM cells would be capable of mediating protective responses against infection. Our previous studies showed that lymphopenia-induced homeostatic memory OT-I CD8 + T cells were capable of L. monocytogenes control (8, 9), and a recent report showed similar potent protection by the VM population that arises spontaneously in intact OT-I mice (16). However, it was not clear whether these findings would correspond to the polyclonal Vβ5 CD8 T cells studied here.…”

“…These cells appear soon after birth in normal mice (12) and have been found to comprise 5-20% of CD8 T cells specific for diverse foreign antigens (11)(12)(13)(14)(15)(16). The finding that VM cells arise at similar frequencies in germ-free mice supports the model that such cells are produced by homeostatic mechanisms, rather than stimulation by environmental or commensal microbes (11).…”

“…Although VM cells constitute 5-20% of the foreign antigenspecific CD8 T-cell population in unprimed mice (11)(12)(13)(14)(15)(16), the very low frequency of precursors for a given MHC/peptide ligand makes functional assessment of VM CD8 T cells challenging. To solve this problem, we used mice expressing the rearranged T cell receptor (TCR) β-chain of the ovalbumin (OVA)-specific OT-I TCR (henceforth called "Vβ5 Tg").…”

Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency

“…B6-Tyr-Cre ERT2 Braf CA Pten lox/lox , -IL-15 ¡/¡ , -IL-15Ra ¡/¡ , and -IL-2Rb (CD122) ¡/¡ mice were described previously. [31][32][33] Mice were housed and bred in specific pathogen-free conditions in the University of Pittsburgh animal facility (Pittsburgh, PA). All animal procedures were performed according to approved protocols and in accordance with recommendations for the proper use and care of laboratory animals.…”