Transcriptional Control of Rapid Recall by Memory CD4 T Cells

Abstract

Memory T cells are distinguished from naive T cells by their rapid production of effector cytokines, although mechanisms for this recall response remain undefined. Here, we investigated transcriptional mechanisms for rapid IFN-γ production by antigen-specific memory CD4 T cells. In naive CD4 T cells, IFN-γ production only occurred following sustained antigen activation and was associated with high expression of the T-bet transcription factor required for Th1 differentiation, and T-bet binding to the IFN-γ promoter as assessed by chromatin immunoprecipitation analysis (ChIP). By contrast, immediate IFN-γ production by antigen-stimulated memory CD4 T cells occurred in the absence of significant nuclear T-bet expression or T-bet engagement on the IFN-γ promoter. We identified rapid induction of NFκB transcriptional activity and increased engagement of NFκB on the IFN-γ promoter at rapid times following TCR stimulation of memory compared to naive CD4 T cells. Moreover, pharmacologic inhibition of NFκB activity or peptide-mediated inhibition of NFκB p50 translocation abrogated early memory T cell signaling and TCR-mediated effector function. Our results reveal a molecular mechanism for memory T cell recall through enhanced NFκB p50 activation and promoter engagement, with important implications for memory T cell modulation in vaccines, autoimmunity and transplantation.

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

“…Several reports have previously linked different members of the canonical and noncanonical NFκB pathway with T-cell memory (12,13,47). Our results confirmed this role and show how NFκB signaling regulates the generation of memory T cells in the context of infection.…”

Human Memory, but Not Naive, CD4+ T Cells Expressing Transcription Factor T-bet Might Drive Rapid Cytokine Production

“…Studies in mouse models have shown that low level stimulation can modulate memory CD4 ϩ T cell function and survival at the recall level, and that a novel biochemical and transcriptional signature is imparted to memory CD4 ϩ T cells enabling efficacious responses (14,23,24). In this study, we present data showing that human memory CD4 ϩ T cells without any stimulation express a high level of T-bet compared with naive CD4 ϩ T cells.…”

“…T-bet is the major transcription factor for the Th1-cell lineage commitment of CD4 ϩ T cells because of its transactivation of the Th1 effector cytokine IFN-␥ (13). Previous studies in a mouse model showed that IFN-␥ production by Ag-stimulated memory CD4 ϩ T cells occurred in the absence of significant nuclear T-bet expression or T-bet engagement on the IFN-␥ promoter (14). In addition to T-bet, STAT-1 and STAT-4 also have important roles in regulating the differentiation of Th1 cells in the presence of IL-12 or IFN-␥.…”

CD4 T Cell Help Is Limiting and Selective during the Primary B Cell Response to Influenza Virus Infection

“…Memory T cells are known to be more sensitive to antigen stimulation due to the presence of clustered T cell receptors on the cell surface and to the reduced dependence on costimulation (49)(50)(51)(52). Accordingly, the memory CD4 T cells evident in the MLN on day 0 of infection proliferated rapidly to high frequencies by day 7, whereas CD4 T cells elicited in the primary response to infection were barely detectable in the draining lymph node.…”