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

Omilusik, Kyla; Best, J Adam; Yu, Bingfei; Goossens, Steven; Weidemann, Alexander; Nguyen, Jessica V.; Seuntjens, Eve; Stryjewska, Agata; Zweier, Christiane; Roychoudhuri, Rahul; Gattinoni, Luca; Bird, Lynne M.; Higashi, Youichirou; Kondoh, Hisato; Huylebroeck, Danny; Haigh, Jody J.; Goldrath, Ananda W.

doi:10.1084/jem.20150194

Cited by 204 publications

(187 citation statements)

References 56 publications

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“…S4B) and pathways (Fig. 4E) involved in cellular activation [that is, spry1 (38), ptger2 (39), and il-7r (40)] and memory differentiation [that is, β-catenin–related genes (41)] are down-regulated in fCD8 T cells, the effect of which would be to increase fCD8 T cell activation.…”

Section: Resultsmentioning

confidence: 99%

Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies

Petrovas

Ferrando‐Martínez

Gerner³

et al. 2017

Sci. Transl. Med.

142

197

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Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.

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Section: Resultsmentioning

confidence: 99%

Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies

Petrovas

Ferrando‐Martínez

Gerner³

et al. 2017

Sci. Transl. Med.

142

197

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“…For example, the most highly expressed transcript in CD154 + cells versus CD154 − cells encodes a cytoskeletal protein called Ermin (ERMN), which is believed to be restricted to oligodendrocytes [31]. Similarly, the most highly expressed gene for a transcription factor in CD154 + versus CD154 − cells encodes Zinc Finger E-Box Binding Homeobox 2 (ZEB2), which has been implicated in CD8 + T cell and myeloid cell function but to our knowledge has not been investigated for its potential functions in CD4 + T cells [32, 33]. …”

Section: Resultsmentioning

confidence: 99%

“…While the function of ERMN in CD4 + T cells or other immune cells is yet to be studied, it is possible that similar to oligodendrocytes, the function of ERMN in these cells is related to cytoskeletal changes during activation. Another transcript that showed high levels of expression in CD154 + cells encoded ZEB2, a two-handed zinc-finger transcription factor that binds DNA at tandem, separated consensus E-box sites [32]. Based on microarray intensities, expression of Zeb2 was highest among all transcription factors in CD154 + versus CD154 − cells from BCG-vaccinated mice.…”

Section: Discussionmentioning

confidence: 99%

“…Based on microarray intensities, expression of Zeb2 was highest among all transcription factors in CD154 + versus CD154 − cells from BCG-vaccinated mice. Recent studies have shown that ZEB2 expression is important for the differentiation of effector and memory CD8 + T cells after infection with lymphocytic choriomeningitis virus [32, 49]. While ZEB2 was shown to be downstream of T-bet, and these two factors co-regulate many of the same genes, it appears that ZEB2 modulates these downstream genes independently.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

Kunnath-Velayudhan

Goldberg

Saini

et al. 2017

The Journal of Immunology

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Analysis of antigen-specific CD4+ T cells in mycobacterial infections at the transcriptome level is informative but technically challenging. While several methods exist for identifying antigen-specific T cells, including intracellular cytokine staining, cell surface cytokine-capture assays, and staining with peptide:MHC-II multimers, all of these have significant technical constraints that limit their usefulness. Measurement of activation-induced expression of CD154 has been reported to detect live, antigen-specific CD4+ T cells but this approach remains underexplored, and to our knowledge has not previously been applied in mycobacteria-infected animals. Here we show that CD154 expression identifies adoptively transferred or endogenous antigen-specific CD4+ T cells induced by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination. We confirmed that antigen-specific cytokine production was positively correlated with CD154 expression by CD4+ T cells from BCG-vaccinated mice, and show that high quality microarrays can be performed from RNA isolated from CD154+ cells purified by cell sorting. Analysis of microarray data demonstrated that the transcriptome of the CD4+ CD154+ cells was distinct from that of CD154− cells, and showed major enrichment of transcripts encoding multiple cytokines and pathways of cellular activation. One notable finding was the identification of a previously unrecognized subset of mycobacteria-specific CD4+ T cells characterized by the production of interleukin-3. Our results support the use of CD154 expression as a practical and reliable method to isolate live, antigen-specific CD4+ T cells for transcriptomic analysis and potentially for a range of other studies in infected or previously immunized hosts.

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“…Increasing levels of inflammation induce graded expression of TFs, including T-bet, ZEB2 and Blimp-1, that cooperatively promote TE-signature gene expression and terminal differentiation (Kaech and Cui, 2012, Dominguez et al, 2015, Shin et al, 2013, Omilusik et al, 2015). Simultaneously, the AKT-mediated inactivation of the TF FOXO1 represses expression of MP-signature genes, including Il7r , Sell , Tcf7 , Lef1 , Bach2 and other memory promoting genes (see references within (Kaech and Cui, 2012, Kim et al, 2013)).…”

Section: Introductionmentioning

confidence: 99%

Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8 + T Cell Terminal Differentiation and Loss of Multipotency

et al. 2017

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SUMMARY Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naïve, MP and TE CD8+ T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro–effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2-deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8+ memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, likely from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic-silencing of pro-memory genes in effector T cells.

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

Abstract: In response to viral infections, activated CD8+ T cells differentiate into terminal effector and memory T cells. This developmental process is controlled by the transcriptional repressor Zeb2, which acts downstream of T-bet.

Cited by 204 publications

References 56 publications

Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies

Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8 + T Cell Terminal Differentiation and Loss of Multipotency

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