An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.
CD25, the high-affinity interleukin-2 (IL-2) receptor alpha chain, is rapidly upregulated by antigen-specific CD8(+) T cells after T cell receptor stimulation. Here, we demonstrate that during an acute viral infection, CD25 expression is quite dynamic-after initial upregulation, a subset of virus-specific T cells sustains CD25 expression longer than the rest. At this time when there is distinct heterogeneity in CD25 expression, examination of the in vivo fate of effector cells revealed that CD25(lo) cells, which are relatively less sensitive to IL-2, preferentially upregulate CD127 and CD62L and give rise to functional long-lived memory cells. In contrast, CD25(hi) cells perceiving prolonged IL-2 signals proliferate more rapidly, are prone to apoptosis, exhibit a more pronounced effector phenotype, and appear to be terminally differentiated. Consistent with this, sustained IL-2 receptor signaling during expansion drove terminal-effector differentiation. These data support the hypothesis that prolonged IL-2 signals during priming promote terminal-effector differentiation.
The data demonstrate, for the first time, that protracted exposure to LDR γ-rays can significantly modify the effects of sSPE protons on critical survival/signalling proteins and immunomodulatory cytokines produced by CD4(+) T cells.
An important question in memory T cell differentiation is understanding the mechanisms that regulate the generation of terminal effector cells that die following antigen clearance versus effector cells that give rise to the long‐lived pool of memory CD8 T cells. Using killer cell lectin‐like receptor G1 as a marker to effectively distinguish terminal effectors from memory precursors, we found that despite their diverse cell fates both subsets possess remarkably similar gene expression profiles and function as equally potent direct ex vivo killer cells, with similar ability for inflammatory cytokine production and granzyme B expression. Interestingly, in addition to these conventional effector CTL characteristics memory precursors also produced IL‐2, a property typically ascribed to naïve or memory cells; thus presenting them as a novel effector subset. On the other hand, terminal effector cells represent a “late leaving” subset of cells that continues to perceive stimulation towards the tail end of antigen clearance, and exhibits an enrichment of the “effector cell signature”. Importantly, curtailing stimulation during the later stages of infection enhanced the generation of long‐lived memory cells. Collectively, these data define a model of memory differentiation wherein effector CD8 T cells that are driven further down the differentiation pathway by continued stimulation towards the later stages of infection become metabolically and functionally unfit for memory lineage. These studies strongly support the classical decreasing potential model of memory differentiation, and further demonstrate that “late leaver” effector cells contribute less towards the long‐lived pool of memory CD8 T cells.
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