In response to intracellular pathogens, CD8 + T cells are activated to proliferate and differentiate into a heterogeneous population of effector T cells, which are armed to eliminate infected cells. After pathogen clearance, the majority of effector CD8 + T cells die; however, a subset survives and differentiates to long-lived memory T cells. Should reinfection occur, these memory cells undergo rapid expansion and redifferentiation into effector cells, providing superior protection compared with naive T cells and protecting the host for decades in many cases (Harty and Badovinac, 2008). The ability to selectively induce T cell memory would provide novel methods for provoking protective immunity and inform vaccine strategies.Identification of effector and memory precursor CD8 + T cells within the effector population is facilitated by their distinct expression of several surface receptors. Both subsets express high levels of CD44, whereas IL-7-receptor-α (CD127) is selectively up-regulated during the transition to long-lived memory cells (Kaech et al., 2003). Killer cell lectin-like receptor G1 (KLRG1) expression is inversely correlated with CD127 expression (Joshi et al., 2007) and identifies, in both mice and humans, a subset of terminally differentiated effector cells that possess limited proliferative potential and a shorter lifespan (Voehringer et al., 2002;Joshi et al., 2007).ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1 hi effector CD8 + T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8 + T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1 hi effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8 + T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8 + T cells. Thus, differential expression of CD127 and KLRG1 identifies two populations of T cells during the peak of an infection: KLRG1 hi CD127 lo cells that consist of shorter-lived effector and effector memory cells and KLRG1 lo CD127 hi effector cells that include the long-lived memory precursors (Kaech and Wherry, 2007;Kallies, 2008). Notably, both populations under...

Memory CD4 + T cells play a pivotal role in mediating long-term protective immunity, positioning them as an important target in vaccine development. However, multiple functionally distinct helper CD4 + T-cell subsets can arise in response to a single invading pathogen, complicating the identification of rare populations of memory precursor cells during the effector phase of infection and memory CD4 + T cells following pathogen clearance and the contraction phase of infection. Furthermore, current literature remains unclear regarding whether a single CD4 + memory T-cell lineage gives rise to secondary CD4 + T helper subsets or if there are unique memory precursor cells within each helper lineage. A majority of T follicular helper (Tfh) cells, which have established memory potential, express Id3, an inhibitor of E protein transcription factors, following acute viral infection. We show that expression of Id3 definitively identified a subset of cells within both the CD4 + Tfh and T helper 1 (Th1) lineages at memory time points that exhibited memory potential, with the capacity for significant re-expansion in response to secondary infection. Notably, we demonstrate that a subset of Th1 cells that survive into the memory phase were marked by Id3 expression and possessed the potential for enhanced expansion and generation of both Th1 and Tfh secondary effector cell populations in a secondary response to pathogen. Additionally, these cells exhibited enrichment of key molecules associated with memory potential when compared with Id3 lo Th1 cells. Therefore, we propose that Id3 expression serves as an important marker to indicate multipotent potential in memory CD4 + T cells.

In this Letter, owing to errors introduced during the proofreading process, the words 'infection with' were missing from the sentence "Furthermore, Runx3 RNAi also impaired T RM cell differentiation in the context of a localized infection with enteric Listeria monocytogenes expressing GP 33-41 (LM-GP 33-41) (Fig. 2b). " In addition, in Fig. 1a, the x-axis label for the bottom right graph should have read "Expression change log 2 (D7 kid/D7 T CM)" rather than "Expression change log 2 (D35 kid/D35 T CM)". In Fig. 1e, the arrow pointing from the spleen to T CM should have been enlarged and aligned with the arrow above, and in the heat map in Fig. 1f 'Irf4' should have been non-italic upright font. These errors have all been corrected in the online versions of the Letter. Supplementary Information to this Corrigendum shows the original uncorrected Fig. 1, for transparency. Supplementary Information is available in the online version of this Corrigendum.

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8 + T cells (TRM) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how TRM confer potent and persistent immunity through partitioning of distinct cellular subsets differing in longevity, effector function, and multipotency. Antigen-specific CD8 + T cells localized to the epithelium of the small intestine are primarily comprised of a shorter-lived effector population most prominent early following both acute viral and bacterial infections, and a longer-lived Id3 hi TRM population that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct TRM states, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal TRM heterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of shortlived and long-lived TRM-like subsets, which share qualities with terminally-exhausted and progenitorexhausted cells, respectively. As the clinical relevance of TRM continues to widen from acute infections to settings of chronic inflammation and malignancy, clarification of the spectrum of phenotypic and functional states exhibited by CD8 + T cells that reside in non-lymphoid tissues will provide a framework for understanding their regulation and identity in diverse pathophysiological contexts.

Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was simultaneously terminally-fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection. Notably, this terminally-differentiated effector memory CD8 T cell population (terminal-Tem) was conflated within the conventional Tem population, prompting redefinition of the classical characteristics of Tem cells. Murine terminal-Tem were transcriptionally, functionally, and developmentally unique compared to Tem cells. Through mass cytometry and single-cell RNAseq analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-Tem population of CD8 T cells that was transcriptionally distinct from Tem and Tcm. A key finding of this study was that parsing of terminal-Tem from conventionally defined Tem challenges classical characteristics of Tem biology, including enhanced presence in lymphoid tissues, robust IL-2 production and recall potential, greater than expected homeostatic fitness, refined transcription factor dependencies, and a distinct molecular phenotype. Classification of terminal-Tem and clarification of Tem biology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.