Early Effector CD8 T Cells Display Plasticity in Populating the Short-Lived Effector and Memory-Precursor Pools Following Bacterial or Viral Infection

Plumlee, Courtney R.; Obar, Joshua J.; Colpitts, Sara L.; Jellison, Evan R.; Haining, W. Nicholas; Lefrançois, Leo; Khanna, Kamal M.

doi:10.1038/srep12264

Cited by 44 publications

(65 citation statements)

References 41 publications

(58 reference statements)

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“…Theoretical analysis of fates of B cells that were activated ex vivo pointed out that stochastic choice between competing, mutually exclusive outcomes in a cell-autonomous manner is sufficient for reproducible, averaged responses in a small population of cells [40]. Nonetheless, T cell expansion and differentiation do not occur in a fully autonomous manner, and are known to be plastic and shaped by several cytokines [2,3,41,42]. This suggests that responding T cells attempt to reduce divergent responses by means of paracrine effects of cytokines, and do not rely solely on the statistical action of the central limit theorem [43].…”

Section: Scaled Accumulation Of Crucial Mediators By Temporal Integramentioning

confidence: 98%

What Scales the T Cell Response?

Mayya

Dustin

2016

Trends in Immunology

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T cells are known to scale their clonal expansion and effector cytokine response according to the dose and strength of antigenic signal so as to balance their role of affecting protection with the intertwined and immunologically driven tissue damage. How T cells achieve this is now beginning to be understood. We underscore temporal integration of digital T cell receptor (TCR) signaling as the basis for achieving scaled response by means of accumulating crucial mediators over time. We also discuss the role of temporally integrated crosstalk between TCR and IL2 signaling in mediating a scaled, coherent, collective response by T cells. Finally, we highlight numerous known and putative regulatory interactions in the transcriptional program that are expected to quantitatively scale the T cell response, and also offer new mechanisms to hitherto unexplained observations.

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Section: Scaled Accumulation Of Crucial Mediators By Temporal Integramentioning

confidence: 98%

What Scales the T Cell Response?

Mayya

Dustin

2016

Trends in Immunology

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“…However, when DNMT3a KO T cells differentiate into terminal effector cells, their fate appears to be "locked in" based on our adoptive transfer experiments. Interestingly, the DNMT3a-mediated effects localize to the early effector cell stage when CD8 + T cells remain susceptible to alteration of their potential fates depending on their current inflammatory milieu (2).…”

Section: Discussionmentioning

confidence: 99%

“…Next, we reasoned that DNMT3a may exert its critical role in CD127 − KLRG1 − early effector cells as they differentiate into either CD127 + KLRG1 − memory precursor cells or CD127 − KLRG1 + terminal effector cells (2,3). To test this possibility, we sorted gp 33-41 -specific CD127 − KLRG1 − early effector cells from day 6 LCMVinfected WT or DNMT3a KO donor mice, adoptively transferred them into synchronously infected host WT mice, and assessed their differentiation in vivo 4 d later.…”

Section: Differentiation Effects Following Loss Of Dnmt3a Expression Arementioning

confidence: 99%

“…Shortly after activation, CD8 + T cells down-regulate CD62L and CD127 and have been termed early effector cells. These further divide and differentiate into CD127 − killer cell lectin-like receptor G1 (KLRG1) + terminal effector and CD127 + KLRG1 − memory precursor cells (2)(3)(4). Several factors have been identified that influence the differentiation and polarization of early effector cells toward either terminal effector cells or memory precursor cells.…”

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confidence: 99%

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De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8⁺T-cell fate decisions following activation

Ladle

Phillips

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

110

105

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DNMT3a is a de novo DNA methyltransferase expressed robustly after T-cell activation that regulates plasticity of CD4 + T-cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8 + T-cell effector and memory fate decisions. Whereas effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T-cell intrinsic manner compared with wild-type animals. Rather than increasing plasticity of differentiated effector CD8 + T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8 + T cells. These data identify DNMT3a as a crucial regulator of CD8 + early effector cell differentiation and effector versus memory fate decisions.antigen-specific T-cell clone undergoes massive proliferation and clonal expansion, generating a heterogeneous population of daughter cells (1). Shortly after activation, CD8 + T cells down-regulate CD62L and CD127 and have been termed early effector cells. These further divide and differentiate into CD127 − killer cell lectin-like receptor G1 (KLRG1) + terminal effector and CD127 + KLRG1 − memory precursor cells (2-4). Several factors have been identified that influence the differentiation and polarization of early effector cells toward either terminal effector cells or memory precursor cells. The initial CD8 + T-cell clonal frequency (5, 6), inflammatory signals driving transcription factor expression (2, 7), cytokine stimulation (8, 9), and transcription factor expression levels (10, 11) all impact the fate of early effector CD8 + T cells. As these T cells are genetically identical, cellular processes of epigenetic regulation would also be predicted to play a key role in determining and perpetuating the fate decisions of individual CD8 + T cells.Epigenetic gene regulation encompasses the heritable covalent DNA and histone posttranslational modifications made in individual cells at specific gene loci that function to regulate the accessibility of these genes within chromatin to transcriptional activation (recently reviewed in ref. 12). Epigenetic regulation within T cells has been studied in detail for individual genes (13, 14) and more recently on the whole genome scale (15-17). These studies have identified patterns of histone marks and DNA methylation that differ across the genome between naïve, activated, and memory T cells and correlate with patterns of gene expression.DNA methylation on the cytosine of CpG dinucleotides in gene promoter regions is associated with silencing gene expression. Of the DNA methyltransferases, only DNA methyltransferase 3a (DNMT3a) and 3b (DNMT3b) are capable of adding de novo CpG methylation marks and thus may dynamically regulate gene silencing. We and others have previously shown that DNMT3a is the dominant DNA methyltransferase act...

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“…However, the differentiation process of virusspecific memory CD8 T cells is far from clearly understood. It is generally accepted that throughout the course of infection, there is considerable heterogeneity in the populations of effector CD8 ϩ T cells, which can be phenotypically separated into different populations, including short-lived effector cells (SLECs) and memory precursor effector cells (MPECs) (33,34). SLECs are short-lived, play an active role in virus clearance, and undergo apoptosis once the pathogen is eliminated.…”

Section: Cd8mentioning

confidence: 99%

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

Liu

Yusi

et al. 2015

J Virol

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Hantaan virus (HTNV) infection can cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. CD8؉ T cells play a critical role in combating HTNV infections. However, the contributions of different CD8 ؉ T cell subsets to the immune response against viral infection are poorly understood. Here, we identified a novel subset of CD8 CD8 T cells play a critical role in combating viral infections. Dramatic cellular changes occur as T cells transition through the following three characteristic phases of an antiviral response: initial activation and expansion, the death phase, and the formation of memory T cells. However, many aspects of these activation and differentiation processes are inadequately understood, particularly in humans. There are several important cell surface molecules that regulate the interactions between immune cells and, moreover, characterize cell differentiation and activation status.Sema4D, also called CD100, was the first immune semaphorin discovered (1) and is involved in several aspects of both humoral and cellular immunity (2-6). CD100 exists in both a membranebound form and a soluble form. Membrane-associated CD100 is expressed preferentially on T cells and weakly on B cells and antigen-presenting cells (APCs) (2, 7). CD72, the receptor for CD100, is expressed primarily on immune system cells and is present on the surface of most APCs and B cells. Interaction between CD72 and CD100 leads to dendritic cell (DC) maturation and cytokine production and enhances B cell activation (7).Because of the involvement of CD100 in the immune response, we hypothesized that CD100 may play an important role in the antiviral CD8 T cell response. However, there is limited information available regarding the role of CD100 in infectious diseases. Eriksson et al. (8) investigated the effects of HIV-1 infection on CD100 expression in T cells, and they observed that a subset of CD8 ϩ T cells lacking membrane-associated CD100 showed decreased functional capacity. Their findings suggested that loss of CD100 expression would most likely lead to dysfunctional immunity in HIV-1 infection. It is well accepted that there are many differences between acute infections and chronic infections. Acute infections usually result in effective antiviral immune responses, while chronic infections are often associated with suboptimal T cell function. Furthermore, HIV infects CD4 ϩ T cells and B cells and has profound pathological effects on the immune system, further confounding the interpretation of T cell dynamics following the acute phase. Therefore, it is important to investigate the functional role of CD100 in the CD8 antiviral response in acute infections.

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Early Effector CD8 T Cells Display Plasticity in Populating the Short-Lived Effector and Memory-Precursor Pools Following Bacterial or Viral Infection

Cited by 44 publications

References 41 publications

What Scales the T Cell Response?

What Scales the T Cell Response?

De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8⁺T-cell fate decisions following activation

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

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Early Effector CD8 T Cells Display Plasticity in Populating the Short-Lived Effector and Memory-Precursor Pools Following Bacterial or Viral Infection

Cited by 44 publications

References 41 publications

What Scales the T Cell Response?

What Scales the T Cell Response?

De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+T-cell fate decisions following activation

CD8lowCD100−T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

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De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8⁺T-cell fate decisions following activation

CD8^lowCD100⁻T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection