The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets

Yang, Cliff Y; Best, J Adam; Knell, Jamie; Yang, Edward; Sheridan, Alison; Jesionek, Adam K; Li, Haiyan S.; Rivera, Richard; Lind, Kristin; D’Cruz, Louise M.; Watowich, Stephanie S.; Murre, Cornelis; Goldrath, Ananda W.

doi:10.1038/ni.2158

Cited by 337 publications

(415 citation statements)

References 50 publications

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“…Among the top canonical pathways identified by IPA were gene networks that were related to T cell receptor signaling and differentiation, further documenting the relationship between Dnmt3a-mediated programming and effector differentiation. Interestingly, our analysis revealed that loci targeted for de novo methylation were significantly associated with the ID2 and ID3 transcriptional axis, two well-established regulators of effector and memory T cell differentiation (Extended data 6c) 18,19 . Collectively, these results demonstrate that downregulation of naïve-associated genes is coupled to acquisition of Dnmt3a mediated de novo DNA methylation programs during development of both MP and TE cells.…”

mentioning

confidence: 89%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

380

350

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Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These resting memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogen, but also have many properties in common with naïve cells, including the ability to migrate to lymph nodes and spleen, and their pluri-potency. Thus, memory cells embody features of both naïve and effector cells, fueling a long-standing debate centered on whether memory T cells develop from effector cells or directly from naïve cells1–4. To better define the developmental path of memory CD8 T cells we investigated changes in DNA methylation programming at naïve and effector genes in virus specific CD8 T cells during acute LCMV infection of mice. Methylation profiling of effector CD8 T cell subsets at day 4 and 8 after infection showed that, rather than retaining a naïve epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naïve-associated genes and became demethylated at loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase, Dnmt3a, at an early stage of effector differentiation strikingly reduced methylation of naïve-associated genes and resulted in faster re-expression of these naïve genes, accelerating memory cell development. Longitudinal phenotypic and epigenetic characterization of virus-specific memory-precursor CD8 T cells transferred into antigen-free mice revealed that their differentiation into memory cells was coupled to cell-division independent erasure of de novo methylation programs and re-expression of naïve-associated genes. These data provide evidence that epigenetic repression of naïve-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells supporting a differentiation model where memory T cells arise from a subset of fate-permissive effector T cells.

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mentioning

confidence: 89%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

380

350

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“…Conversely, expression of eomesodermin (Eomes), B cell lymphoma-6 (Bcl6), T cell factor-7 (Tcf7), Id3, forkhead box O 1 (Foxo1), and Stat3 promote development of memory CD8 + T cells and their progenitors (Ichii et al, 2002(Ichii et al, , 2004Jeannet et al, 2010;Zhou et al, 2010;Cui et al, 2011;Yang et al, 2011;Hess Michelini et al, 2013;Kim et al, 2013;Tejera et al, 2013). However, little is known about how these transcription factors interact or affect each other's expression or function to develop distinct subsets of CTLs with diverse cell fates.…”

Section: The Transcription Factors Zeb2 and T-bet Cooperate To Programentioning

confidence: 99%

“…by Prdm1), inhibitor of DNA binding 2 (Id2), and signal transducer and activator of transcription 4 (Stat4) have been identified as critical drivers of TE cell differentiation (Joshi et al, 2007;Kallies et al, 2009;Rutishauser et al, 2009;Yang et al, 2011;Mollo et al, 2013;Shin et al, 2013). Conversely, expression of eomesodermin (Eomes), B cell lymphoma-6 (Bcl6), T cell factor-7 (Tcf7), Id3, forkhead box O 1 (Foxo1), and Stat3 promote development of memory CD8 + T cells and their progenitors (Ichii et al, 2002(Ichii et al, , 2004Jeannet et al, 2010;Zhou et al, 2010;Cui et al, 2011;Yang et al, 2011;Hess Michelini et al, 2013;Kim et al, 2013;Tejera et al, 2013).…”

Section: The Transcription Factors Zeb2 and T-bet Cooperate To Programentioning

confidence: 99%

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

Dominguez¹,

Guan²,

Marshall³

et al. 2015

J Cell Biol

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“…Differential abundance of Id3 2 virus-specific CD8 + T cells in acute and chronic infection Expression of the transcriptional regulator Id3 is downregulated in CD8 + T effector cells upon acute infection (27). To examine the role of Id3 during chronic viral infection, we compared its expression in virus-specific CD8 + T cells from mice infected with either 200 or 10 6 PFU of the Docile strain of LCMV.…”

Section: Resultsmentioning

confidence: 99%

“…), high Id3 expression marks cells with a higher potential to become long-lived memory cells, whereas Id3 expression is absent in short-lived effector cells (27). In accordance, Id3-deficient CD8 + T cells do not properly differentiate into long-lived memory cells upon acute infection, and CD8 + T cells with an enforced Id3 expression show increased persistence due to increased expression of genes that regulate DNA replication and repair (27,28). Id proteins function as negative regulators of the basic helix-loop-helix E protein transcription factors E2A (with its splice variants E12 and E47), HEB, and E2-2 (23).…”

mentioning

confidence: 99%

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Menner

Rauch

Aichele

et al. 2015

The Journal of Immunology

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Sustained Ag persistence in chronic infection results in a deregulated CD8+ T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8+ T cells. Yet, the underlying transcriptional mechanisms regulating CD8+ T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8+ T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3− virus-specific CD8+ T cells were less abundant, whereas the absolute numbers of Id3+ virus-specific CD8+ T cells were equal in chronic and acute infection. Phenotypically, Id3− and Id3+ cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3− cells were 2B4+, almost all Id3+ cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3−2B4+ cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4+ virus-specific CD8+ T cells by decreasing susceptibility to Fas/Fas ligand–mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8+ T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8+ T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8+ T cells to prevent immunopathology.

show abstract

The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets

Cited by 337 publications

References 50 publications

Effector CD8 T cells dedifferentiate into long-lived memory cells

Effector CD8 T cells dedifferentiate into long-lived memory cells

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

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

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