Virtual memory cells: a consequence of self-affinity-linked naïve CD8 T cell heterogeneity (LYM5P.703)

Abstract Memory phenotype (MP), CD44hi CD49dlo CD8 T cells are found in nearly all mice—lymphoreplete, pathogen naïve, and even TCR transgenics. The presence of MP was long thought to be due to environmental pathogen exposure (or, in the case of transgenics, heterologous immunity to same), but studies establishing the presence of these cells in germ-free mice suggested that this was not the case. These cells, dubbed Virtual Memory (VM), are of special relevance due to their increased effector functioning, and, in contrast to other MP CD8 T cells, develop in the periphery with a dependence on IL-15. Our recent studies have determined that VM cells develop in a manner reminiscent of lymphopenic homeostatic expansion, whereby the highest self-affinity T cells (as measured by CD5) interact with available IL-15 to turn into VM cells. This indicates that the naïve CD8 T cell pool is not as homogeneous as usually assumed, and RNA sequencing has further confirmed the heterogeneity of the CD8 naïve T cell pool (separated on CD5). The sequencing has further implicated VM cells in mediating CD8 bystander protection, and ongoing studies suggest that this is indeed the case, with the VM bystander effects being IL-15 dependent.