Upstream eventSuppression of T cell activation
Increase, Increased susceptibility to infection
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection||adjacent||High||Not Specified|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
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
To protect the infection from different pathogens, different types of immune response depending on the pathogens are required.
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 (reviewed by Soares et al. (Soares et al., 2017)).
Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection.
Recipients of liver transplants treated with FK506 that strongly suppress T cell function were found to have suffered from bacterial, viral, and fungal infections (Alessiani et al. 1991, Fung et al. 1991). Complications from infection as a side-effect of administering FK506 was found to be similar to that of cyclosporin A (Ekberg et al. 2007).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Alessiani, M., Kusne, S., Martin, M., et al., 1991. Infections in adult liver transplant patients under FK 506 immunosuppression. Transplant Proc 23, 1501-1503.
Ekberg, H., Grinyo, J., Nashan, B., et al., 2007. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 7, 560-570
Fung, J.J., Todo, S., Tzakis, A., et al., 1991. Current status of FK 506 in liver transplantation. Transplant Proc 23, 1902-1905.
Soares, M.P., Teixeira, L., Moita, L.F., 2017. Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17, 83-96.