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,
* Departments of Pathology,
Immunobiology, and
Dermatology, Yale University School of Medicine, New Haven, CT 06520 and
Medizinische Universitätsklinik 3, Kardiologie, Universität Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Human microvascular endothelial cells (ECs) constitutively express MHC class II in peripheral tissues, the function of which remains unknown. In vitro assays have established that the recognition of EC MHC class II can affect cytokine expression, proliferation, and delayed transendothelial migration of allogeneic memory, but not naive, CD4+ T cells. Previously, we have shown that effector memory CD4+ T cells will rapidly transmigrate in response to the inflammatory chemokine IFN-
-inducible protein-10 (IP-10) in a process contingent upon the application of venular levels of shear stress. Using two models that provide polyclonal TCR signaling by ECs in this flow system, we show that TCR engagement antagonizes the rapid chemokine-dependent transmigration of memory CD4+ T cells. Inhibitor studies suggest that TCR signaling downstream of Src family tyrosine kinase(s) but upstream of calcineurin activation causes memory CD4+ T cell arrest on the EC surface, preventing the transendothelial migration response to IP-10.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is funded by National Institute of Health Grant P01-HL070295 (to J.S.P.).
2 Address correspondence and reprint requests to Dr. Jordan S. Pober, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06520. E-mail address: jordan.pober{at}yale.edu
3 Abbreviations used in this paper: EC, endothelial cell; 41BBL, 41BB ligand; DAPI, 4',6'-diamidino-2-phenylindole; EM, effector memory; ICOSL, ICOS ligand; IP-10, IFN--inducible protein-10; OX40L, OX40 ligand; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; SDF, stromal cell-derived factor; TEM, transendothelial migration; TSST-1, toxic shock syndrome toxin-1.
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  T. D. Manes and J. S. Pober Antigen Presentation by Human Microvascular Endothelial Cells Triggers ICAM-1-Dependent Transendothelial Protrusion by, and Fractalkine-Dependent Transendothelial Migration of, Effector Memory CD4+ T Cells J. Immunol., June 15, 2008; 180(12): 8386 - 8392. [Abstract] [Full Text] [PDF]
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D. A. Rao, K. J. Tracey, and J. S. Pober IL-1{alpha} and IL-1beta Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response J. Immunol., November 15, 2007; 179(10): 6536 - 6546. [Abstract] [Full Text] [PDF]
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