Dynamic equilibrium of B7-1 dimers and monomers differentially affects immunological synapse formation and T cell activation in response to TCR/CD28 stimulation

Sumeena Bhatia, Kristine Sun, Steven C. Almo, Stanley G. Nathenson, Richard J. Hodes

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Abstract

Under steady-state conditions, B7-1 is present as a mixed population of noncovalent dimers and monomers on the cell surface. In this study, we examined the physiological significance of this unique dimer-monomer equilibrium state of B7-1. We demonstrate that altering B7-1 to create a uniformly covalent dimeric state results in enhanced CD28-mediated formation of T cell-APC conjugates. The enhanced T cell-APC conjugate formation correlates with persistent concentration of signaling molecules PKC-θ and lck at the immunological synapse. In contrast, T cell acquisition of B7-1 from APCs, an event that occurs as a consequence of CD28 engagement with B7-1/B7-2 and is thought to play a role in the dissociation of T cell-APC conjugates, is highly reduced when B7-1 is present in the covalently dimeric state. The ability of covalently dimeric and wild type B7-1 to costimulate Ag-specific T cell proliferation was also assessed. In contrast to the enhanced ability of dimeric B7-1 to support conjugate formation and early parameters of T cell signaling, sensitivity to competitive inhibition by soluble CTLA-4-Ig indicated that the covalent dimeric form of B7-1 is less efficient in costimulating T cell proliferation. These findings suggest a novel model in which optimal T cell costimulatory function of B7-1 requires high-avidity CD28 engagement by dimeric B7-1, followed by dissociation of these noncovalent B7-1 dimers, facilitating downregulation of CD28 and internalization of B7-1. These events regulate signaling through TCR/CD28 to maximize T cell activation to proliferation.

Original languageEnglish (US)
Pages (from-to)1821-1828
Number of pages8
JournalJournal of Immunology
Volume184
Issue number4
DOIs
StatePublished - Feb 15 2010

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Immunological Synapses
T-Lymphocytes
Cell Proliferation
Down-Regulation

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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Dynamic equilibrium of B7-1 dimers and monomers differentially affects immunological synapse formation and T cell activation in response to TCR/CD28 stimulation. / Bhatia, Sumeena; Sun, Kristine; Almo, Steven C.; Nathenson, Stanley G.; Hodes, Richard J.

In: Journal of Immunology, Vol. 184, No. 4, 15.02.2010, p. 1821-1828.

Research output: Contribution to journalArticle

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