Differential interferon-γ production by naive and memory-like CD8 T cells

CD8 T cells play a crucial role in immune responses to virus infections and tumors. Naïve CD8 T lymphocytes after TCR stimulation undergo differentiation into CTLs and memory cells, which are essential sources of IFN-γ. We investigated IFN-γ production by CD8 T cell subsets found in nonimmune mice. A minor fraction of in vitro TCR-stimulated CD8 T cells produce IFN-γ, and it is regulated at the transcriptional level. Antigen inexperienced C57BL/6 mice present the coexistence of 2 populations. The main population exhibits a CD44^low CD122^low profile, which is compatible with naïve lymphocytes. The minor expresses a phenotype of immunologic memory, CD44^hi CD122^hi . Both subsets are able to produce IL-2 in response to TCR activation, but only the memory-like population is responsible for IFN-γ production. Similar to memory CD8 T cells, CD44^hi CD8⁺ T cells also present a higher level of the transcriptional factor Eomes and a lower level of T-bet (Tbx21) mRNA than CD44^low CD8⁺ T cells. The presence of the CD44^hi CD8⁺ T cell population in nonimmune OT-I transgenic mice reveals that the population is generated independently of antigenic stimulation. CpG methylation is an efficient epigenetic mechanism for gene silencing. DNA methylation at posttranscriptional CpG sites in the Ifng promoter is higher in CD44^low CD8⁺ T cells than in CD44^hi CD8⁺ T cells. Thus, memory-like CD8 T cells have a distinct epigenetic pattern in the Ifng promoter and can rapidly produce IFN-γ in response to TCR stimulation.