Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

Richard, Alison F.

doi:10.3389/fimmu.2022.949423

Cited by 10 publications

(12 citation statements)

References 156 publications

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“…Lineage tracing studies have previously identified diversity in the expansion and differentiation of single T cells through primary and recall responses (Buchholz et al, 2016). Cellular heterogeneity may also contribute to the dynamic nature of adaptive immune responses to respond to a breadth of antigens (Richard, 2022; Wong and Germain, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that the accumulation of varying levels of TCR signaling in naive T cells in the steady state can influence changes in T cell gene expression. This feature of tonic TCR signaling also raises the possibility that variable gene expression patterns in response to tonic TCR signaling result in functional heterogeneity within the naive T cell population (Eggert and Au-Yeung, 2021; Richard, 2022). This concept is consistent with models proposing that T cell responsiveness depends on previously experienced TCR signals (Huseby and Teixeiro, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Eggert

Zinzow-Kramer

et al. 2023

Preprint

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The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8+ T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigated how naive CD8+ T cells that experienced relatively low or high levels of TCR signaling in response to self-antigens respond to stimulation with foreign antigens. A transcriptional reporter of Nr4a1 (Nur77-GFP) revealed substantial heterogeneity of the amount of TCR signaling naive CD8+ T cells accumulate in the steady state. Nur77-GFPHIcells exhibited diminished T cell activation and secretion of IFN γ and IL-2 relative to Nur77-GFPLOcells in response to agonist TCR stimulation. Differential gene expression analyses revealed upregulation of genes associated with acutely stimulated T cells in Nur77-GFPHIcells but also increased expression of negative regulators such as the phosphatase Sts1. Responsiveness of Nur77-GFPHIcells to TCR stimulation was partially restored at the level of IFN γ secretion by deficiency of Sts1 or the ubiquitin ligase Cbl-b. Our data suggest that extensive accumulation of TCR signaling during steady state conditions induces a recalibration of the responsiveness of naive CD8+ T cells through gene expression changes and negative regulation, at least in part, dependent on Sts1 and Cbl-b. This cell-intrinsic negative feedback loop may allow the immune system to limit the autoreactive potential of highly self-reactive naive CD8+ T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Eggert

Zinzow-Kramer

et al. 2023

Preprint

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“…CD8+ T cells play critical roles in adaptive immunity. Antigen stimulation drives naïve CD8+ T cells to rapidly undergo a step-by-step process of early activation, clonal expansion and differentiation ( 62 – 65 ). In addition to early activation, IRF4 participates in the entire process of differentiation and function of effector CD8+ T cells ( 66 , 67 ).…”

Section: Effect Of Irf4 On the Differentiation And Function Of Cd8+ T...mentioning

confidence: 99%

“…Next, IRF4 combined with AP1 family TFs form an activating IRF4/AP1 complex, which integrates TCR and costimulatory signals to induce the production of a series of effector cytokines. After antigen clearance, the expression of IRF4 decreased, followed by an increase in expression of stemness-like gene T cell factor 7 ( Tcf7 ; encoding TCF1) ( Figure 3B ), and further producing memory precursor cells (MPECs) and TCF1+ memory-like T cells to rapidly function in the secondary response ( 64 , 65 ) ( Figure 3A ).…”

Section: Effect Of Irf4 On the Differentiation And Function Of Cd8+ T...mentioning

confidence: 99%

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Liang²,

Li³

et al. 2023

Front. Immunol.

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The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

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“…However, tonic TCR signals can alter chromatin accessibility and influence the expression of several genes at the transcriptional or the protein level in T cells (6)(7)(8)(9). This feature of tonic TCR signaling also raises the possibility that variable gene expression patterns in response to tonic TCR signaling result in functional heterogeneity within the naive T cell population (10,11). How the intensity of tonic TCR signals helps shape the responsiveness of naive T cells to subsequent foreign antigen stimulation remains unresolved (3).…”

Section: Introductionmentioning

confidence: 99%

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

Eggert,

Zinzow-Kramer,

et al. 2024

Sci. Signal.

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Naive T cells experience tonic T cell receptor (TCR) signaling in response to self-antigens presented by major histocompatibility complex (MHC) in secondary lymphoid organs. We investigated how relatively weak or strong tonic TCR signals influence naive CD8 + T cell responses to stimulation with foreign antigens. The heterogeneous expression of Nur77-GFP, a transgenic reporter of tonic TCR signaling, in naive CD8 + T cells suggests variable intensities or durations of tonic TCR signaling. Although the expression of genes associated with acutely stimulated T cells was increased in Nur77-GFP HI cells, these cells were hyporesponsive to agonist TCR stimulation compared with Nur77-GFP LO cells. This hyporesponsiveness manifested as diminished activation marker expression and decreased secretion of IFN-γ and IL-2. The protein abundance of the ubiquitin ligase Cbl-b, a negative regulator of TCR signaling, was greater in Nur77-GFP HI cells than in Nur77-GFP LO cells, and Cbl-b deficiency partially restored the responsiveness of Nur77-GFP HI cells. Our data suggest that the cumulative effects of previously experienced tonic TCR signaling recalibrate naive CD8 + T cell responsiveness. These changes include gene expression changes and negative regulation partially dependent on Cbl-b. This cell-intrinsic negative feedback loop may enable the immune system to restrain naive CD8 + T cells with higher self-reactivity.

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Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

Cited by 10 publications

References 156 publications

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

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Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

Cited by 10 publications

References 156 publications

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Cbl-b mitigates the responsiveness of naive CD8 + T cells that experience extensive tonic T cell receptor signaling

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Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling