Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling.
Lymphocyte antigen receptors are responsible for inducing the opposite responses of immunity or tolerance. How the correct polarity of antigen receptor signaling is encoded has been an enduring enigma. Here we summarize recent advances defining key scaffolding molecules, CARMA1 (also known as CARD11) and the Cbl family of ubiquitin ligases, required for either immunogenic or tolerogenic signaling by antigen receptors. These scaffolding proteins may determine the polarity of response to antigen by promoting assembly around antigen receptors of competing multiprotein signal complexes: immunosomes versus tolerosomes. Each of the factors that influence immunogenicity or tolerogenicity--stage of lymphocyte differentiation, concurrent engagement of inhibitory or costimulatory receptors, extent of receptor crosslinking, and prior antigen experience--may be integrated in lymphocytes through their capacity to influence the probability of assembling immunosomes versus tolerosomes.
Jun
Jesse E
JE
Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.
Goodnow
Christopher C
CC
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020013:Calcium Signaling / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011946:Receptors, Antigen / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D011946:Receptors, Antigen; D044767:Ubiquitin-Protein Ligases; C426242:CARD11 protein, human; D006162:Guanylate Cyclase