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Suppression of T cell activation leads to Increase, Increased susceptibility to infection
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Impaired IL-1R1 signaling leading to increased susceptibility to infection||adjacent||High||High||Yutaka Kimura (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Normal T cell and B cell function is indispensable for host defense mechanism.
Evidence Supporting this KER
The experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).
The activation of NF-κB plays a principal role in the immunological function of IL-1R signalling. NF-κB plays a crucial role in the activation of dendritic cells as well as T cells. In dendritic cells, the activation of the canonical NF-κB pathway in response to pro-inflammatory stimuli, such as cytokines including IL-1a or IL-1b and TLR ligands, stimulate the maturation of dendritic cells with enhanced antigen presenting function. The inhibition of NF-κB suppress antigen presenting function of dendritic cells, resulting in suppression of T cell activation (reviewed by Reinhard et al (Reinhard et al., 2012) and van Delft et al (van Delft, Huitema and Tas, 2015).
In T cells, NF-kB can be activated by several pathways of signal transduction. Although the engagement of the TCR by major histocompatibility complex (MHC) plus antigen is a main stream of NF-kB activation in T cells, the stimulation of T cells by IL-1 activates NF-kB as already described before. Once in the nucleus, NF-kB governs the transcription of numerous genes involved in T cell survival, proliferation, and effector functions (Paul and Schaefer, 2013). Although CD4 T cells are able to commit to Th1, Th2 and Th17 lineages in the absence of IL-1R signaling at steady state, these committed CD4 T cells are unable to effectively secrete their cytokines upon TCR ligation. Namely, IL-1 is indispensable for CD4 T cell effector function (Lin et al., 2015).
To protect the infection from different pathogens, different types of immune response depending on the pathogens are required (reviewed by Soares et al. (Soares et al., 2017)).
1). Type 1 immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 (TH1) signature cytokine interferon-γ (IFNγ) has a central role in triggering cytotoxic mechanisms including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), activation of CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity.
2) Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves type 2 immunit. Pathogen neutralization is achieved via different mechanisms controlled by TH2 signature cytokines, including interleukin-4 (IL-4), IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin (TSLP), IL-25 or IL-33, secreted by damaged cell. TH2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia.
3) TH17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis. Activation of TH17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. TH17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase.
Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection.
Uncertainties and Inconsistencies
Luster et al (1993) demonstrated that Concanavalin A response of splenocytes showed the linear dose-response relationship with the host resistnace to Listeria monocytogenes or Streptococcus pneumoniae.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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