Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation

Adjuvants are commonly used in vaccines to augment immune response, but how the inflammatory cytokines elicited by adjuvants directly influence effector and memory CD8 T cell differentiation remains poorly characterized. Here, we used a peptide-pulsed dendritic cell (DC) vaccination model to examine the role of primary cytokines, IL-12 and IFN gamma, elicited by CpG-B adjuvant on CD8 T cell priming and memory CD8 T cell development. During DC vaccination, Simultaneous exposure to antigen and a heterologous Listeria infection, CpG-B or IL-12 enhanced a portion of the effector CD8 T cells to expand and differentiate to a larger extent. Simultaneously, this also decreased their ability to become long-lived memory CD8 T cells. However, development of memory CD8 T cells and their precursors was largely unaffected by the additional inflammatory cytokines. Moreover, IL-12 production by the antigen-presenting cell (APC) was not required during DC+CpG vaccination or Listeria infection, but rather 'bystander' macrophages and DCs appealed to be the physiologically relevant cellular sources of this cytokine. Furthermore, IFN-gamma induced by CpG was required hi vivo for optimal production of IL 12, which in turn, influenced effector CD8 T cell longevity. Together, these findings demonstrate the importance of an interconnected multicellular network between APCs, naive T cells and bystander cells of the innate immune system that regulate effector and memory CD8 T cell development during vaccination. (C) 2009 Elsevier Ltd. All rights reserved.