A road map of memory CD8+ T cell functional imprinting and fitness

Abstract

Abstract Previous studies established that TCR signaling strength determines the size of CD8+ T cell expansion and memory pool. Here we hypothesized that TCR signaling strength further modulates the functional features of memory CD8+ T cells. We immunized mice transferred with naïve OT-I cells, which recognize the Ovalbumin (Ova)-derived epitope SIINFEKL, with Listeria monocytogenes expressing different variants, exposing OT-I cells to various TCR signaling strength. Transcriptomic analysis at early times after priming revealed that compared to OT-I cells primed with strong TCR signals, those primed with weak TCR signals upregulated genes involved in cell cycle (IL-2) and type I IFN response, suggesting that TCR signaling strength could determine how CD8+ T cells respond to cytokines at the time of priming. We postulated that disrupting cytokine signaling in T cells primed with weak TCR signals could alter memory T cell fate. As proposed, OT-I memory cells primed with weak TCR signals and lacking IL-2 or type I IFN cytokine signaling (Ifnar−/−, Il2ramut/mut) failed to re-expand upon secondary challenge compared to WT counterparts. Moreover, transcriptomic and epigenetic analyses of WT or Il2ramut/mut OT-I memory cells primed with strong versus weak TCR signals revealed that while gene expression remained similar, chromatin accessibility was significantly different. TCR and IL-2 signaling together regulate an epigenetic landscape reflecting a broad functional fitness of memory CD8+ T cells, whereas TCR signaling selectively imprinted an epigenetic landscape related to metabolism. These results suggest that epitope selection for effective CD8+ T cell vaccine design is pivotal to modulate the functional programming of memory T cells.