Keeping LAT Out

Science's STKE  30 May 2006:
Vol. 2006, Issue 337, pp. tw177
DOI: 10.1126/stke.3372006tw177

T cell anergy prevents self-reactive T cells that escape elimination in the thymus from responding. T cell anergy is associated with decreased interleukin 2 (IL-2) production and decreased proliferation in response to antigen-specific stimulation. In a cultured cell system and an in vivo model, Hundt et al. show that, although phosphorylation of the tyrosine kinase ZAP-70 is not impaired, phosphorylation of the ZAP-70 substrate linker of activated T cells (LAT) is decreased. LAT serves as a scaffold recruiting various downstream effectors to the immunological synapse. Thus, lack of LAT phosphorylation prevents activation of phospholipase C-γ1 (PLC-γ1) and phosphatidylinositol 3-kinase (PI3K). Indeed, Hundt et al. observed decreased coimmunoprecipitation of LAT with the p85 subunit of PI3K and decreased phosphorylation of PLC-γ1 in the anergic T cells. There was no decrease in LAT abundance in the anergic cells; however, fluorescence microscopy experiments showed that LAT was selectively excluded from the immunological synapse, and cell fractionation studies showed that LAT was specifically excluded from detergent-resistant membrane fractions. In both models of anergy, palmitoylation of LAT, which is required for localization to detergent-resistant membranes, was reduced. The palmitoylation defect was specific for LAT; palmitoylation of Fyn was unaffected. Thus, exclusion of LAT from the immunological synapse by depalmitoylation of LAT promotes the formation of an immunological synapse with altered signaling properties in anergic T cells compared with the signaling properties of activated T cells (see Lineberry and Fathman for discussion).

M. Hundt, H. Tabata, M.-S. Jeon, K. Hayashi, Y. Tanaka, R. Krishna, L. De Giorgio, Y.-C. Liu, M. Fukata, A. Altman, Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. Immunity 24, 513-522 (2006). [PubMed]

N. Lineberry, C. G. Fathman, T cell anergy: Where it's LAT. Immunity 24, 501-503 (2006). [PubMed]