Linking PI3K signalling with TNFRSF
TNFRSF binding is generally held to signal through NFkB pathways - but in many cases have been shown to increase pAKT and/or have effects negated through inhibition of PI3K/AKT.
General principles: TNFRSF need to cluster/oligomerise to signal. - soluble ligand trimers tend not to signal well unless artificially oligomerised or unless receptors are pre-clustered. - clustering = translocation into detergent-insoluble membrane (DIM) compartments, mediated by TRAF2 --> both translocation and TRAF2 required for signalling (studied in OX40). - PIP2 enriched in DIM; in T cells some fraction of PI3K/PDK1 constitutively associate with DIM. - Formation of ‘signallosome’ in DIM: (OX40) TRAF2, IKK, CARMA1-BCL10-MALTI1 (NFkB machinery), PKC-theta, p85-PI3K/AKT***. *** TCR signalling not required for inclusion but required for activation - regulatory measures specific to T cells; role in bringing PI3K close to TCR/CD28 signallosome?
EXAMPLES
TNFR2 (ligand TNF) - sustains pAKT following TCR/CD28 stimulation. - favours Teff development over iTreg differentiation? TNFa neutralisation reduces iTreg; pAKT associates with Smad3/inhibits TGFb-driven Foxp3 transcription.
OX40 (ligand OX40L) - AKT loss of function resembles OX40KO; constitutively active AKT rescues OX40 deficiency. - also antagonises iTreg differentiation.
4-1BB (ligand 4-1BBL) - enhances T cell proliferation, antagonised by AKT inhibition. - directly or indirectly enhances IFNg production --> inhibits iTreg differntiation.
HVEM (ligand LIGHT) - deletion reduces AKT activity --> reduces T cell survival --> rescued by constitutive AKT activity.
DR3 (ligand TL1A) (autocrine signalling in activated T cells) - observed to be highly expressed on Tregs and not Tcon in allergic lung inflammation (mouse asthma), agonist antibody 4C12 selectively enhances Treg proliferation, blocked by AKT inhibition https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947231/ - TL1A-expressing tumours elicit strong CD8 response https://www.ncbi.nlm.nih.gov/pubmed/21688261 - Sustained TL1A expression in DCs triggers intestinal goblet hyperplasia, increases Treg turnover but decreases suppressive function https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053556/ - Other examples of high TL1A in autoimmune settings, blocking reduces severity; equal expression on Tregs and activated Tcons; enhancement of Th1/Th2 responses; inhibition of iTreg differentiation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763597/?report=classic#B65
Fig 2.
Source: So, Takanori (Croft, Michael) 2013, Frontiers in Immunology. Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675380/