Abstract
Following an infection, naïve CD8 T cells are stimulated by dendritic cells (DC) displaying pathogen-derived peptides on MHC class I molecules (signal 1) and costimulatory molecules (signal 2). Additionally, pathogen-induced inflammatory cytokines also act directly on the responding CD8 T cells to regulate their expansion and differentiation. In particular, both type I interferons (IFNs) and IL-12 have been described as critical survival signals (signal 3) for optimal CD8 T cell accumulation during the expansion phase. Furthermore, expansion in numbers of antigen-specific CD8 T cells is coupled with their acquisition of effector functions to combat the infection. However, it still remains unclear whether these same cytokines also regulate the effector/memory differentiation program of the CD8 T cell response in vivo. Here, we demonstrate that defective signaling by either type I IFNs or IL-12 to the responding CD8 T cells impairs maximal expansion in response to DC immunization + CpG ODN, but neither of these cytokines is essential to regulate the effector/memory differentiation program. In addition, lack of direct IL-12 signaling to CD8 T cells accelerates the development of central memory phenotype in both primary and secondary antigen-specific memory CD8 T cells.
Highlights
The naive CD8 T cell repertoire for any specific pathogen–peptide ranges between 10 and 1000 cells per mouse (Blattman et al, 2002)
Type I IFN signaling in CD8 T cells is most critical for numerical expansion in the lymphocytic choriomeningitis virus infection model, whereas IL-12 serves as the critical signal 3 for CD8 T cells responding to Listeria monocytogenes (LM) and vaccinia infection (Kolumam et al, 2005; Thompson et al, 2006; Xiao et al, 2009)
Direct signaling by signal 3 inflammatory cytokines, type I IFN, or IL-12, to CD8 T cells promotes their expansion after dendritic cells (DC) + CpG DNA immunization The requirement of direct type I IFN or IL-12 signaling for optimal CD8 T cell expansion depends critically on the inflammatory cytokines produced by the specific pathogen in the study (Aichele et al, 2006; Thompson et al, 2006; Xiao et al, 2009)
Summary
The naive CD8 T cell repertoire for any specific pathogen–peptide ranges between 10 and 1000 cells per mouse (Blattman et al, 2002). Type I IFN signaling in CD8 T cells is most critical for numerical expansion in the lymphocytic choriomeningitis virus infection model, whereas IL-12 serves as the critical signal 3 for CD8 T cells responding to Listeria monocytogenes (LM) and vaccinia infection (Kolumam et al, 2005; Thompson et al, 2006; Xiao et al, 2009) It remains unclear if these same critical signal 3 inflammatory cytokines directly regulate the commitment of responding CD8 T cells to effector or memory differentiation in vivo. Dissociating the inflammatory signals from the activating signal 1 and 2 would provide a better understanding of how specific cytokines regulate the commitment of the responding CD8 T cells to effector or memory differentiation
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