MAdCAM-1 costimulates T cell proliferation exclusively through integrin alpha4beta7, whereas VCAM-1 and CS-1 peptide use alpha4beta1: evidence for "remote" costimulation and induction of hyperresponsiveness to B7 molecules.
We have analyzed the effects of the alpha4 integrin ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), and the fibronectin CS-1 splice variant on T cell activation. Immobilized MAdCAM-1 and VCAM-1 IgG-Fc chimeras and a fibronectin CS-1 peptide efficiently costimulate T cell proliferation when antigen presentation is mimicked by anti-CD3 antibody. VCAM-1-Fc and fibronectin CS-1, which are adhesive ligands for both the alpha4beta1 and alpha4beta7 integrins, medicate T cell costimulation exclusively through integrin alpha4beta1, but not through alpha4beta7. The inability of VCAM-1-Fc to costimulate via alpha4beta7 suggests that cell adhesion per se is insufficient, and that exquisite recognition and activation events must be triggered. MAdCAM-1-Fc mediates costimulation exclusively via alpha4beta7, and can both synergize with and induce hyperresponsiveness to the classical costimulator B7-2. MAdCAM-1-Fc and VCAM-1-Fc, but not B7-2, effectively costimulate when immobilized on sites spatially distant from the anti-CD3 antibody ("remote" costimulation). In vitro, the relative potencies of the CAM were VCAM-1-Fc> ICAM-1-Fc> MAdCAM-1-Fc > B7-Fc, except at high concentrations where ICAM-1 was the most potent. Features of costimulatory CAM revealed by this study have important implications for the design of immunotherapeutic vaccine strategies to combat cancer and infection.
Lehnert
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K
Department of Molecular Medicine, School of Medicine and Health Sciences, University of Auckland, New Zealand.
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D000069594:Abatacept; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology*; D060908:CTLA-4 Antigen; D015815:Cell Adhesion Molecules; D005353:Fibronectins / Q000502:physiology*; D006801:Humans; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000502:physiology*; D039441:Integrin alpha4; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000502:physiology*; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015815:Cell Adhesion Molecules; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D005353:Fibronectins; D018796:Immunoconjugates; D007136:Immunoglobulins; D007376:Interleukin-2; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; C504268:Madcam1 protein, rat; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D000069594:Abatacept