Multiple genetic programs contribute to CD4 T cell memory differentiation and longevity by maintaining T cell quiescence

While memory T-cells (Tmem) represent a hallmark of adaptive immunity, and despite extensive characterization of CD8+ Tmem, little is known about regulation of CD4+ Tmem cell survival. In this study, we analyzed antigen-specific CD4+T cell memory populations in mice and human to characterize their unique genetic and surface phenotypes. First, using microarray technology, we studied dynamic gene expression of antigen specific CD4+ T cells during infection, memory differentiation, and survival up to nearly a year. In murine CD4+T cells, we observed reduced expression of genes that induce cell proliferation and increased expression of anti-apoptotic and pro-survival genes. Importantly, these genetic programs revealed multiple transmembrane markers enriched in the murine CD4+ Tmem population. We verified the ability of these markers to denote CD4+ Tmem populations using influenza vaccination, and observed enrichment of these surface markers in antigen-specific cells. Finally, we tested the ability of these markers to denote human memory CD4+ T cells. We found that their expression exclusively co-localized with existing human memory marker CD45R0, and that sorting of cells positive for these markers recovered more responding antigen-specific CD4+T cells than the general CD4+T cell population. In sum, this study presents unique gene signatures of long-lived murine CD4+ Tmem cells along with new surface markers some of which were validated in human. The new information can improve our assessment of CD4 memory T cells can be incorporated for novel therapeutics and vaccine design. The study intended to examine the distinct genetic programs utilized by antigen-specific CD4+T cells differentiating into long-lived memory cells. Using Agilent microarray technology, we monitored gene expression in mouse CD4+ T cells undergoing various stages of differentiation post-immunization at times 0 and 9 days, 5 weeks, 6- and 10.5 months. The gene expression of CD4+ T cells of naive female DO11.10 mice was profiled as a control reference.