Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

Abstract

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...

The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

“…In this study, we found that high amounts of T-bet induced Zeb2 mRNA expression and that ZEB2 was critical for the transcriptional programming of TE cell differentiation. To our knowledge, this study, along with that of Omilusik et al (2015), is the first to describe the function of ZEB2 in T cells. Overall, these data suggest that ZEB2 and T-bet enforce terminal effector differentiation through their cooperation by simultaneously inducing TE and repressing MP cell gene expression.…”

Extrafollicular responses in humans and SLE

“…At least in the mouse, Bcell-intrinsic T-bet expression is also necessary for the production of IgG2A and effective antiviral humoral immunity. 99,100 DN2cells also express high amounts of ZEB2, a TF that acts cooperatively with T-bet to promote effector differentiation and inhibit memory differentiation in cytotoxic T cells 101,102. Importantly, despite sharing IL-21 receptor expression with naive cells, only naive cells express high levels of several repressors of effector differentiation including BACH2 which can directly repress PRDM1/BLIMP1,103 and FOXO1 which inhibits T-bet-mediated effector function in CD8 T cells 104.…”

“…Importantly, despite sharing IL-21 receptor expression with naive cells, only naive cells express high levels of several repressors of effector differentiation including BACH2 which can directly repress PRDM1/BLIMP1,103 and FOXO1 which inhibits T-bet-mediated effector function in CD8 T cells 104. In distinction to DN2 cells, SWM and DN1 express high levels of TCF7 a TF that is repressed by T-bet/Zeb2, promotes central memory differentiation, and inhibits effector differentiation 102. In addition to the T-Bet/ Zeb2-regulated network, DN2 cells are characterized by high levels of expression of IRF4 and IRF4-regulated genes, in particular, of IRF4 target genes enriched in plasma cells.…”

Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate

“…In oligodendrocyte precursors, where Zeb2 expression is low in abundance, activated Smads bind the coactivator histone acetyltransferase p300 and activate the expression of negative regulatory genes such as Id2 and Hes1; by contrast, in differentiating oligodendrocytes, expression of Olig1 and Olig2 induces Zeb2, which binds Smad-p300 complexes and represses expression of Id2 and Hes1 (24). Within the hematopoietic system, Zeb2 cooperates with Tbx21 (T-bet) to promote terminal maturation of natural killer (NK) cells and CD8 + T cells (25)(26)(27), and its inactivation results in broadly dysregulated hematopoiesis with prominent neutrophilia and loss of B cells and monocytes (28).…”