Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.
Many ligands of adhesion molecules mediate costimulation of T cell activation. The generality of this emerging concept is best determined by using model systems which exploit physiologically relevant ligands. We developed such an "antigen-specific" model system for stimulation of resting CD4+ human T cells using the following purified ligands: (a) major histocompatibility complex class II plus the superantigen Staphylococcus enterotoxin A, to engage the T cell receptor (TCR); (b) adhesion proteins vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1), to provide potential cell surface costimulatory signals; and (c) recombinant interleukin 1 beta (rIL-1 beta)/rIL-6 as costimulatory cytokines. In this biochemically defined system, we find that resting CD4+ T cells require costimulation in order to respond to TCR engagement. This costimulation can be provided by VCAM-1 or ICAM-1; however adhesion alone is not sufficient since ELAM-1 mediates adhesion but not costimulation. The cytokines IL-1 beta and IL-6 by themselves cannot mediate costimulation, but augment the adhesion ligand-mediated costimulation. Direct comparison with the model of TCR/CD3 engagement by CD3 monoclonal antibody demonstrated comparable costimulatory requirements in both systems, thereby authenticating the commonly used CD3 model. The costimulation mediated by the activation-dependent interaction of the VLA-4 and LFA-1 integrins with their respective ligands VCAM-1 and ICAM-1 leads to increased IL-2R alpha (CD25) expression and proliferation in both CD45RA+ CD4+ and CD45RO+ CD4+ T cells. The integrins also regulate the secretion of IL-2, IL-4, and granulocyte/macrophage colony-stimulating factor. In contrast the activation-independent adhesion of CD4+ T cell to ELAM-1 molecules does not lead to T cell stimulation as measured by proliferation, IL-2R alpha expression, or cytokine release. These findings imply that adhesion per se is not sufficient for costimulation, but rather that the costimulation conferred by the VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions reflects specialized accessory functions of these integrin pathways. The new finding that VLA-4/VCAM-1 mediates costimulation adds significance to observations that VCAM-1 is expressed on a unique set of potential antigen-presenting cells in vivo.
van Seventer
G A
GA
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Newman
W
W
Shimizu
Y
Y
Nutman
T B
TB
Tanaka
Y
Y
Horgan
K J
KJ
Gopal
T V
TV
Ennis
E
E
O'Sullivan
D
D
Grey
H
H
D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002478:Cells, Cultured; D019040:E-Selectin; D004768:Enterotoxins / Q000276:immunology* / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006681:HLA-D Antigens / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D018799:Intercellular Adhesion Molecule-1; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013211:Staphylococcus aureus; D013601:T-Lymphocytes / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D004768:Enterotoxins; D006681:HLA-D Antigens; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; C026066:enterotoxin A, Staphylococcal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor