The integrin-associated protein (IAP, CD47) is a 50-kD plasma membrane protein with a single extracellular immunoglobulin variable (IgV)-like domain, a multiply membrane-spanning segment, and alternatively spliced short cytoplasmic tails. On neutrophils, IAP has been shown to function in a signaling complex with β3 integrins. However, the function of IAP on T cells, which express little or no β3 integrin, is not yet defined. Here, we show that mAbs recognizing IAP can enhance proliferation of primary human T cells in the presence of low levels of antiCD3, but have no effect on T cell proliferation on their own. Together with suboptimal concentrations of anti-CD3, engagement of IAP also enhances IL-2 production in Jurkat cells, an apparently integrin-independent function of IAP. Nonetheless, costimulation by IAP ligation requires cell adhesion. IAP costimulation does not require CD28. Furthermore, anti-IAP, but not anti-CD28, synergizes with suboptimal anti-CD3 to enhance tyrosine phosphorylation of the CD3 ζ chain and the T cell–specific tyrosine kinase Zap70. Ligation of human IAP transfected into the hemoglobin-specific 3.L2 murine T cell hybridoma costimulates activation for IL-2 secretion both with anti-CD3 and with antigenic peptides on antigen-presenting cells (APCs). Moreover, ligation of IAP but not CD28 can convert antagonist peptides into agonists in 3.L2 cells. Using costimulation by IAP ligation as an assay to analyze the structure–function relationships in IAP signaling, we find that both the extracellular and multiply membrane-spanning domains of IAP are necessary for synergy with the antigen receptor, but the alternatively spliced cytoplasmic tails are not. These data demonstrate that IAP ligation initiates an adhesiondependent costimulatory pathway distinct from CD28. We hypothesize that anti-IAP generates the costimulatory signal because it modulates interactions of the IgV domain with other plasma membrane molecules; this in turn activates effector functions of the multiply membrane-spanning domain of IAP. This model may have general significance for how IAP functions in cell activation.
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6 January 1997
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January 01 1997
Costimulation of T Cell Activation by Integrin-associated Protein (CD47) Is an Adhesion-dependent, CD28-independent Signaling Pathway
Martina I. Reinhold,
Martina I. Reinhold
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
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Frederik P. Lindberg,
Frederik P. Lindberg
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
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Gilbert J. Kersh,
Gilbert J. Kersh
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
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Paul M. Allen,
Paul M. Allen
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
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Eric J. Brown
Eric J. Brown
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
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Martina I. Reinhold
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
Frederik P. Lindberg
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
Gilbert J. Kersh
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
Paul M. Allen
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
Eric J. Brown
From the *Departments of Medicine, Molecular Microbiology, and Cell Biology and Physiology; and the ‡Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
Address correspondence to Dr. Eric J. Brown, Campus Box 8051, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110.
This work was supported by grants from the National Institutes of Health and the Washington University– Monsanto Cooperative Agreement.
1Abbreviations used in this paper: CT, cytoplasmic tail; IAP, integrin-associated protein; IgV, immunoglobulin variable.
Received:
July 01 1996
Revision Received:
October 21 1996
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 185 (1): 1–12.
Article history
Received:
July 01 1996
Revision Received:
October 21 1996
Citation
Martina I. Reinhold, Frederik P. Lindberg, Gilbert J. Kersh, Paul M. Allen, Eric J. Brown; Costimulation of T Cell Activation by Integrin-associated Protein (CD47) Is an Adhesion-dependent, CD28-independent Signaling Pathway. J Exp Med 6 January 1997; 185 (1): 1–12. doi: https://doi.org/10.1084/jem.185.1.1
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