The tyrosine kinase Itk suppresses CD8+ memory T cell development in response to bacterial infection

Huang, Fei; Huang, Weishan; Briggs, Jessica; Chew, Tina W.; Bai, Y.; Deol, Simrita; August, Avery

doi:10.1038/srep07688

Cited by 11 publications

(16 citation statements)

References 36 publications

(50 reference statements)

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“…ITK has been shown to regulate the strength of the TCR signal during T cell activation (28)(29)(30)(31). We have previously shown that reducing TCR signal strength via deletion of ITK leads to an increase in the proportion of Ag-specific CD8 + MPECs (32). This data support the theory that TCR signal strength inversely regulates the development of memory T cells.…”

supporting

confidence: 78%

TCR Signal Strength and Antigen Affinity Regulate CD8+ Memory T Cells

Solouki

Huang

Elmore

et al. 2020

The Journal of Immunology

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CD8+ T cells play a critical role in adaptive immunity, differentiating into CD8+ memory T cells that form the basis of protective cellular immunity. Vaccine efficacy is attributed to long-term protective immunity, and understanding the parameters that regulate development of CD8+ T cells is critical to the design of T cell–mediated vaccines. We show in this study using mouse models that two distinct parameters, TCR signal strength (regulated by the tyrosine kinase ITK) and Ag affinity, play important but separate roles in modulating the development of memory CD8+ T cells. Unexpectedly, our data reveal that reducing TCR signal strength along with reducing Ag affinity for the TCR leads to enhanced and accelerated development of CD8+ memory T cells. Additionally, TCR signal strength is able to regulate CD8+ T cell effector cytokine R production independent of TCR Ag affinity. Analysis of RNA-sequencing data reveals that genes for inflammatory cytokines/cytokine receptors are significantly altered upon changes in Ag affinity and TCR signal strength. Furthermore, our findings show that the inflammatory milieu is critical in regulating this TCR signal strength–mediated increase in memory development, as both CpG oligonucleotide treatment or cotransfer of wild-type and Itk−/− T cells eliminates the observed increase in memory cell formation. These findings suggest that TCR signal strength and Ag affinity independently contribute to CD8+ memory T cell development, which is modulated by inflammation, and suggest that manipulating TCR signal strength along with Ag affinity, may be used to tune the development of CD8+ memory T cells during vaccine development.

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supporting

confidence: 78%

TCR Signal Strength and Antigen Affinity Regulate CD8+ Memory T Cells

Solouki

Huang

Elmore

et al. 2020

The Journal of Immunology

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“…Inducible T cell kinase (ITK) plays an important role in the maintenance of Th2 CD4+ cells and memory CD8+ T cells and is known to be inhibited by ibrutinib (5). However, Itk −/− CD8+ memory T cells (in comparison to naïve CD8+ T cells) demonstrate normal recall responses to bacterial infection in terms of frequency and functionality and this is compatible with our findings (19). The impact of ibrutinib on the induction of primary immune responses mediated by naïve T cells deserves further investigation.…”

Section: Discussionsupporting

confidence: 91%

Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia

Parry

Mirajkar

Cutmore³

et al. 2019

Front. Immunol.

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Chronic Lymphocytic Leukaemia (CLL) is associated with immune suppression and susceptibility to infection. CD8 + T cell numbers are increased and demonstrate elevated expression of PD-1 and impaired function. The mechanisms driving these features of exhaustion are uncertain but are likely to include chronic immune recognition of tumor and/or infectious agents. We investigated the number, phenotype and function of total and virus-specific CD8+ T cells in 65 patients with CLL and 14 patients undergoing long-term ibrutinib therapy (median 21 months). Ibrutinib substantially reduced the number of both CD3+ T cells and CD8+ T cells. Importantly, this was associated with a reduction in PD-1 expression on CD8+ T cells (median 28 vs. 24%; p = 0.042) and 3.5 fold increase in cytokine production following mitogen stimulation. The influence of ibrutinib on antigen-specific CD8+ T cell function was assessed by HLA-peptide tetramers and revealed increased IFNγ and TNFα cytokine responses following stimulation with CMV or EBV peptides together with a 55% reduction in the frequency of "inflated" virus-specific CD8+ T cells. These findings reveal that long-term ibrutinib therapy is associated with substantial reversal of T cell exhaustion in B-CLL and is likely to contribute to the reduced infection risk seen in association with this agent.

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“…The second one (memory potential, survival) would be similar to the MPEC population. This is consistent with the litterature, since Tbet is known to favour the development of SLEC, to the detriment of MPEC [7,8,9].…”

Section: Cellular Dynamics Arise From Cellular Heterogeneitysupporting

confidence: 86%

“…Transcription factors Tbet and Eomesodermin (Eomes) appear to play critical roles in the acquisition of effector and memory phenotypes. It has been shown that the expression of Tbet induces the development of SLEC and represses the development of MPEC profiles [7,8,9]. Eomes is not involved in the SLEC versus MPEC fate choice [10,11].…”

Section: Introductionmentioning

confidence: 99%

Model-based assessment of the Role of Uneven Partitioning of Molecular Content on Heterogeneity and Regulation of Differentiation in CD8 T-cell Immune Responses

Girel

Arpin

Marvel

et al. 2018

Preprint

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Activation of naive CD8 T-cells can lead to the generation of multiple effector and memory subsets. Multiple parameters associated with activation conditions are involved in generating this diversity that is associated with heterogeneous molecular contents of activated cells. Naive cell polarisation upon antigenic stimulation and the asymmetric division that results are known to be a major source of heterogeneity and cell fate regulation. The consequences of stochastic uneven partitioning of molecular content upon subsequent divisions remain unclear. Here we aim at studying the impact of uneven partitioning on molecular-content heterogeneity and then on the immune response dynamics at the cellular level. To do so, we introduce a multiscale mathematical model of the CD8 T-cell immune response in the lymph node. In the model, cells are described as agents evolving and interacting in a 2D environment while a set of differential equations, embedded in each cell, models the regulation of intra and extracellular proteins involved in cell differentiation. Based on the analysis of in silico data at the single cell level, we show that immune response dynamics can be explained by the molecular-content heterogeneity generated by

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The tyrosine kinase Itk suppresses CD8+ memory T cell development in response to bacterial infection

Cited by 11 publications

References 36 publications

TCR Signal Strength and Antigen Affinity Regulate CD8+ Memory T Cells

TCR Signal Strength and Antigen Affinity Regulate CD8+ Memory T Cells

Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia

Model-based assessment of the Role of Uneven Partitioning of Molecular Content on Heterogeneity and Regulation of Differentiation in CD8 T-cell Immune Responses

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