Abstract
The defining feature of memory T cells is the capacity for rapid effector function upon restimulation through the T cell antigen receptor (TCR), although the signaling mechanisms controlling memory recall remain undefined. We hypothesized that enhanced transcription factor activation regulated the distinct TCR-coupled functional responses in naive and memory CD4 T cells. We generated memory CD4 T cells by in vitro-priming of naive CD4 T cells from DO11.10 transgenic mice, adoptive transfer into mouse hosts, and recovery 4-8 weeks post-transfer. OVA-specific memory CD4 T cells produced high levels of IFN-γ early (6hrs) after antigen stimulation, compared to IFN-γ production after 24-48hrs stimulation of OVA-specific naive CD4 T cells. Early IFN-γ production by antigen-stimulated memory CD4 T cells occurred in the absence of upregulation of the T-bet transcription factor, while IFN-γ production following naive CD4 T cell activation was associated with high T-bet expression. Chromatin immunoprecipitation (ChIP) analysis revealed that NFκB, but not T-bet was bound to the IFN-γ promoter in memory CD4 T cells early after TCR stimulation. In addition, expression of the active nuclear p50 subunit of NFκB was increased in resting and activated memory versus naive CD4 T cells, and inhibition of NFκB activity impaired early memory T cell recall. These results reveal a molecular mechanism for immediate recall responses in memory CD4 T cells through enhanced NFκB activity.
