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Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation
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||Moderate||Yutaka Kimura (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
NF-kB plays a crucial role in the activation of dendritic cells as well as T cells. In dendritic cells, the activation of the canonical NF-kB 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-kB 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. The engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activation motif (ITAM) phosphorylation by the Src family kinases, FYN and leukocyte C-terminal src kinase (LCK). Phosphorylated CD3 activates the T cell specific tyrosine kinase, zeta-chain associated protein kinase (ZAP-70), which ultimately trigger calcium release and protein kinase (PK)C activation, respectively. Activation of a specific PKC isoform, PKCμ, connects the above described TCR proximal signaling events to distal events that ultimately lead to NF-kB activation. Importantly, PKCm activation is also driven by engagement of the T cell co-stimulatory receptor CD28 by B7 ligands on antigen presenting cells (APCs). In addition, 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).
Evidence Supporting this KER
Mice lacking NF-kB p50 are unable to effectively clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).
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)
RelB deficient mice had an impaired cellular immunity, as observed in contact sensitivity reaction (Weih et al., 1995).
Delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1b-deficient and IL-1a/b-deficient mice. Lymph node cells derived from antigen-sensitized IL-1b-deficient and IL-1a/b-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. (Nambu et al., 2006).
Uncertainties and Inconsistencies
Interferon-γ (IFN-γ) production in response to CMV-infected fibroblasts was reduced under the influence of MG132 in a dose-dependent manner. A marked reduction was observed at 0.5 μM. Likewise, CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132 (Wang et al., 2011).
Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro (Orciuolo et al., 2007).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Fiedler, M.A., Wernke-Dollries, K., Stark, J.M. (1998), Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132. Am J Respir Cell Mol Biol 19: 259-268, 10.1165/ajrcmb.19.2.3149
Lin, D., Lei, L., Zhang, Y., et al. (2015), Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45: 2084-2098, 10.1002/eji.201445195
Nambu, A., Nakae, S., Iwakura, Y. (2006), IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 18: 701-712, 10.1093/intimm/dxl007
Nishioka, C., Ikezoe, T., Jing, Y., et al. (2008), DHMEQ, a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells. Immunology 124: 198-205, 10.1111/j.1365-2567.2007.02755.x
Ohkusu-Tsukada, K., Ito, D., Takahashi, K. (2018), The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice. Int Arch Allergy Immunol 176: 91-100, 10.1159/000488155
Orciuolo, E., Galimberti, S., Petrini, M. (2007), Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro. Leuk Res 31: 1026-1027, 10.1016/j.leukres.2006.09.002
Reinhard, K., Huber, M., Lohoff, M., et al. (2012), The role of NF-kappaB activation during protection against Leishmania infection. Int J Med Microbiol 302: 230-235, 10.1016/j.ijmm.2012.07.006
Sha, W.C., Liou, H.C., Tuomanen, E.I., et al. (1995), Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80: 321-330,
van Delft, M.A., Huitema, L.F., Tas, S.W. (2015), The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur J Clin Invest 45: 529-539, 10.1111/eci.12430
Wang, Y., Sun, B., Volk, H.D., et al. (2011), Comparative study of the influence of proteasome inhibitor MG132 and ganciclovir on the cytomegalovirus-specific CD8(+) T-cell immune response. Viral Immunol 24: 455-461, 10.1089/vim.2011.0038
Weih, F., Carrasco, D., Durham, S.K., et al. (1995), Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80: 331-340,
Yu, A., Malek, T.R. (2001), The proteasome regulates receptor-mediated endocytosis of interleukin-2. J Biol Chem 276: 381-385, 10.1074/jbc.M007991200