TCR Signaling Quality Counts

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

The immunological synapse (IS) is the point of contact between T cell receptors (TCRs) and antigenic peptide–bearing major histocompatability complexes (MHCs) on an antigen-presenting cell (APC). The IS consists of a central supramolecular activation cluster (cSMAC), in which TCRs predominate, and a surrounding, ringlike peripheral SMAC (pSMAC), in which adhesion molecules are found. The role of the cSMAC in the IS is controversial. It may serve as an area of enhanced TCR signaling or as the site from which TCRs are internalized (see Valitutti). In addition, clustered TCRs can signal in the pSMAC, and TCR signaling can occur before the cSMAC is established. Through a combination of computational modeling, imaging experiments, and Western blotting analysis of tyrosine-phosphorylated signaling proteins, emerski et al. have extended their previous studies to examine whether TCRs signal in the cSMAC. Although high doses of antigen stimulated TCR signaling predominantly in the pSMAC, low doses of antigen resulted in increased TCR signaling in the cSMAC. At low doses of antigen, more TCR signaling occurred in the pSMAC than in the cSMAC at early time points, but at later time points, this balance shifted in favor of TCR signaling in the cSMAC. High doses of antigen stimulated TCR signaling in the cSMAC if TCR internalization was pharmacologically blocked, whereas enforced formation of the cSMAC (through the activation of the transfected NKG2D receptor) increased TCR signaling in response to low doses of antigen. Together, these data suggest that the cSMAC serves to either inhibit or enhance TCR signaling depending on whether the antigenic stimulus is strong or weak.

S. emerski, J. Das, E. Giurisato, M. A. Markiewicz, P. M. Allen, A. K. Chakraborty, A. S. Shaw, The balance between T cell receptor signaling and degradation at the center of the immunological synapse is determined by antigen quality. Immunity 29, 414-422 (2008). [PubMed]

S. Valitutti, Immunological synapse: Center of attention again. Immunity 29, 384-386 (2008). [PubMed]

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