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Nikolaev2019 - Immunobiochemical reconstruction of influenza lung infection-melanoma skin cancer interactions

ABSTRACT: This is a mathematical mechanistic immunobiochemical model that incorporates T cell pathways that control programmed cell death protein 1 (PD-1) expression. A core component of the model is a kinetic motif, termed a PD-1 Double Incoherent Feed-Forward Loop (DIFFL), which reflects known interactions between IRF4, Blimp-1, and Bcl-6.

SUBMITTER: Johannes Meyer

PROVIDER: BIOMD0000000865 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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Publications

Immunobiochemical Reconstruction of Influenza Lung Infection-Melanoma Skin Cancer Interactions.

Nikolaev Evgeni V EV Zloza Andrew A Sontag Eduardo D ED

Frontiers in immunology 20190128

It was recently reported that acute influenza infection of the lung promoted distal melanoma growth in the dermis of mice. Melanoma-specific CD8+ T cells were shunted to the lung in the presence of the infection, where they expressed high levels of inflammation-induced cell-activation blocker PD-1, and became incapable of migrating back to the tumor site. At the same time, co-infection virus-specific CD8+ T cells remained functional while the infection was cleared. It was also unexpectedly found ...[more]

PMID: 30745900

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PD-L1 alteration in lung cancer affects tumorigenicity lung tumors

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Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes â such as BATF â that inhibit T cell function. PD-1 expressing Jurkat cells were cultured for 18 hours with beads coated with antibodies to CD3 and CD28, with our without an antibody to PD-1.

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