KLRG1+ Memory CD8 T cells Combine Properties of Short-lived Effectors and Long-lived Memory

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Abstract An effective memory CD8 T cell response must generate cells that respond robustly to antigen re-encounter to produce an effective recall response while also maintaining a stable pool of durable cells in the absence of antigen. During the effector response KLRG1+ CD127low cells are described predominantly as short-lived effectors that will undergo apoptosis during the contraction phase or downregulate KLRG1. However, we have shown that long-lived KLRG1+ CD127low T cells are still present at the memory phase, and that these T cells (termed long-lived effector cells or LLEC) display robust protective function during acute re-challenge with bacteria or viruses. Here, we find that LLEC are derived exclusively from KLRG1+ effector cells, and that this contributes a substantial fraction of the resulting memory pool. Our work challenges the concept that the KLRG1+ CD127low population is dominated by short-lived cells, shows that KLRG1 downregulation is not a prerequisite to become a long-lived protective memory T cell, and highlights the diversity within the memory compartment. Furthermore, using single-cell sequencing we demonstrate that LLEC are not simply a remnant effector population that has failed to undergo initial contraction, but rather a discrete population of T cells with a distinct transcriptional signature that shares characteristics of both early effectors (GzmA, GzmB, Klrg1, Cx3cr1, Zeb2), long-lived memory cells (Bcl2, Il7r, Aqp9, Dmrta1), and a pattern of inhibitory receptors associated with NK cell function (Klrc1, Klre1, Klrd1). Overall, the unique transcriptional profile of LLEC translates to an identity encompassing the hybrid characteristics of effector-like cytotoxicity paired with longevity.