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Article
Nature Immunology  5, 791 - 799 (2004)
Published online: 11 July 2004; | doi:10.1038/ni1095

CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse

Qi-Jing Li1, 8, Aaron R Dinner2, 7, 8, Shuyan Qi2, 3, 8, Darrell J Irvine1, 7, Johannes B Huppa1, 4, Mark M Davis1, 4 & Arup K Chakraborty2, 3, 5, 6

1  Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.

2  Department of Chemistry, University of California, Berkeley, California 94720, USA.

3  Department of Chemical Engineering, University of California, Berkeley, California 94720, USA.

4  Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.

5  Biophysics Graduate Group, University of California, Berkeley, California 94720, USA.

6  Physical Biosciences and Materials Science Divisions, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

7  Present addresses: Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, USA (A.R.D.) and Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA (D.J.I.).

8  These authors contributed equally to this work.

Correspondence should be addressed to Mark M Davis mdavis@cmgm.stanford.edu or Arup K Chakraborty arup@uclink.berkeley.edu
How T cells respond with extraordinary sensitivity to minute amounts of agonist peptide and major histocompatibility complex (pMHC) molecules on the surface of antigen-presenting cells bearing large numbers of endogenous pMHC molecules is not understood. Here we present evidence that CD4 affects the responsiveness of T helper cells by controlling spatial localization of the tyrosine kinase Lck in the synapse. This finding, as well as further in silico and in vitro experiments, led us to develop a molecular model in which endogenous and agonist pMHC molecules act cooperatively to amplify T cell receptor signaling. At the same time, activation due to endogenous pMHC molecules alone is inhibited. A key feature is that the binding of agonist pMHC molecules to the T cell receptor results in CD4-mediated spatial localization of Lck, which in turn enables endogenous pMHC molecules to trigger many T cell receptors. We also discuss broader implications for T cell biology, including thymic selection, diversity of the repertoire of self pMHC molecules and serial triggering.

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Nature Immunology
ISSN: 1529-2908
EISSN: 1529-2916
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