Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|Pralnacasan (VX-740) and Belnacasan (VX-765)|
|IL-1 receptor antagonist（IL-1Ra）(Anakinra)|
|anti-IL-1b antibody (Canakinumab)|
|Stressor:491 soluble IL-1R (Rilonacept)|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|All life stages||High|
Key Event Description
T cells are key orchestrators of the response against pathogens and are also fundamental in maintaining self-tolerance. A number of clinically important conditions have been described in which T-cell functions are altered, as in AIDS or upon immunosuppression for solid organ transplantation. T-cell progenitors differentiate in the thymus into immature T cells that acquire the expression of the T-cell receptor (TCR), which recognizes antigen peptides from pathogens presented along with major histocompatibility complex (MHC). In addition to the TCR, T cells are characterized by expression of the co-receptor molecules CD4 and CD8 on their cell surface. CD4+ T cells, also called T helper (Th) cells, recognize antigen/MHC-II complexes on antigen presenting cells (APCs) and coordinate the activation of other immune cells including B cells, macrophages, etc.
Therefore, CD4+ T cells are crucial for coordination of the immune response and for the elimination of invading pathogens. On the other hand, CD8+ T cells, referred to as T cytotoxic cells, recognize antigen/MHC-I complexes and are responsible for the killing of pathogen-infected cells.
Recognition of MHC/peptide complexes by the TCR and the co-receptors results in T-cell activation (for a review, see (Smith-Garvin et al., 2009)). Signalling via the TCR is further supported by co-stimulatory (e.g. CD28) and accessory (e.g. integrins) molecules. Upon TCR ligation, members of the Src family kinases Lck and Fyn phosphorylate the immunoreceptor tyrosine-based signalling motifs (ITAMs) located within the TCR-associated CD3 and ζ chains. This event results in the recruitment of the tyrosine kinase ζ chain–associated protein kinase of 70 kDa (ZAP-70) to the receptor. ZAP-70 is in turn activated and further phosphorylates the linker for activation of T cells (LAT), a transmembrane adaptor molecule that further assembles a complex leading to Ca2+ flux, Ras and protein kinase C (PKC) activation. These events ultimately culminate in gene transcription, proliferation and differentiation of T cells.
T-cell activation and differentiation depends on APCs such as dendritic cells (DCs), macrophages and B cells. Among them, DCs are highly specialized in antigen presentation and in T-cell priming (Lanzavecchia and Sallusto, 2001). DCs act as sentinels in the body where they capture antigens. Danger signals such as microbial products or cytokines from injured tissue activate DCs, which in turn migrate to secondary lymphoid organs, where they allow initiation of the immune response (Vega-Ramos et al., 2014). The nature of the stimulus dictates which kind of immune response will be set in motion (Macagno et al., 2007). Therefore, depending on the insult affecting a given tissue, different subsets of DCs can be generated that in turn are able to coordinate the differentiation of a particular Th subset.
To date, the following Th subsets have been described: Th1, Th2, Th9, Th17, Th22, Tfh (follicular helper T cells), Tr1 (type 1regulatory T cells) and Treg (regulatory T cells), each possessing a specific function in the elimination of pathogens. (reviewed by Simeoni et al. (Simeoni et al., 2016))
In the process of antigen presentation by DCs, macrophages or B cells, T cell activation is impaired.
How It Is Measured or Detected
T cell activation can be evaluated by measuring IL-2 production by ELISA or T cell proliferation by incorporation of the analysis of CFSE labeled T cells or [3H]thymidineincorporation.
Domain of Applicability
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent. Again, age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).
These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.
Evidence for Perturbation by Stressor
Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.
Lanzavecchia, A., Sallusto, F., 2001. Regulation of T cell immunity by dendritic cells. Cell 106, 263-266.
Macagno, A., Napolitani, G., Lanzavecchia, A., Sallusto, F., 2007. Duration, combination and timing: the signal integration model of dendritic cell activation. Trends Immunol 28, 227-233.
Simeoni, L., Thurm, C., Kritikos, A., Linkermann, A., 2016. Redox homeostasis, T cells and kidney diseases: three faces in the dark. Clin Kidney J 9, 1-10.
Smith-Garvin, J.E., Koretzky, G.A., Jordan, M.S., 2009. T cell activation. Annu Rev Immunol 27, 591-619.
Vega-Ramos, J., Roquilly, A., Asehnoune, K., Villadangos, J.A., 2014. Modulation of dendritic cell antigen presentation by pathogens, tissue damage and secondary inflammatory signals. Curr Opin Pharmacol 17, 64-70.
Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., Bravo, R., 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.