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The T Cell Receptor Triggering Apparatus Is Composed of Monovalent or Monomeric Proteins
Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
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2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 37, 31993-32001 p.Article in journal (Refereed) Published
Abstract [en]

Understanding the component stoichiometry of the T cell antigen receptor (TCR) triggering apparatus is essential for building realistic models of signal initiation. Recent studies suggesting that the TCR and other signaling-associated proteins are preclustered on resting T cells relied on measurements of the behavior of membrane proteins at interfaces with functionalized glass surfaces. Using fluorescence recovery after photo-bleaching, we show that, compared with the apical surface, the mobility of TCRs is significantly reduced at Jurkat T cell/glass interfaces, in a signaling-sensitive manner. Using two biophysical approaches that mitigate these effects, bioluminescence resonance energy transfer and two-color coincidence detection microscopy, we show that, within the uncertainty of the methods, the membrane components of the TCR triggering apparatus, i.e. the TCR complex, MHC molecules, CD4/Lck and CD45, are exclusively monovalent or monomeric in human T cell lines, implying that TCR triggering depends only on the kinetics of TCR/pMHC interactions. These analyses also showed that constraining proteins to two dimensions at the cell surface greatly enhances random interactions versus those between the membrane and the cytoplasm. Simulations of TCR-pMHC complex formation based on these findings suggest how unclustered TCR triggering-associated proteins might nevertheless be capable of generating complex signaling outputs via the differential recruitment of cytosolic effectors to the cell membrane.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2011. Vol. 286, no 37, 31993-32001 p.
National Category
Biochemistry and Molecular Biology
Research subject
Natural sciences
Identifiers
URN: urn:nbn:se:his:diva-5519DOI: 10.1074/jbc.M111.219212ISI: 000294726800008Scopus ID: 2-s2.0-80052730531OAI: oai:DiVA.org:his-5519DiVA: diva2:511775
Available from: 2012-03-23 Created: 2012-03-01 Last updated: 2013-04-10Bibliographically approved

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