Dynamic equilibrium of B7-1 dimers and monomers differentially affects immunological synapse formation and T cell activation in response to TCR/CD28 stimulation.
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- 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.
Bhatia
Sumeena
S
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sun
Kristine
K
Almo
Steven C
SC
Nathenson
Stanley G
SG
Hodes
Richard J
RJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016466:CHO Cells; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D054992:Immunological Synapses / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D011948:Receptors, Antigen, T-Cell