Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells.
Interactions between T cells and antigen-presenting cells (APCs) are the first step in the induction of an adaptive immune response. Here, we show that CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are actively recruited to the antigen-induced dendritic cell (DC)-T-cell contact zone. Moreover, ALCAM-blocking antibodies interfere with DC-T-cell conjugate formation, demonstrating that CD6-ALCAM binding is essential for stable T-cell-APC contact. We now demonstrate that besides their role in establishing initial contacts, CD6-ALCAM interactions are also required during the proliferative phase of the T-cell response; the presence of CD6-blocking antibodies or recombinant ALCAM-Fc proteins results in a strong and sustained inhibition of T-cell proliferation. Furthermore, simultaneous crosslinking of CD6 and CD3 induces enhanced proliferation and transcriptional activity to a similar level as observed after CD3 and CD28 co-crosslinking, demonstrating that CD6 is an important costimulatory molecule. The stability of ALCAM-CD6 binding, which contrasts with transient homotypic ALCAM-ALCAM interactions, further supports the long-lasting effects observed on T-cell proliferation. Taken together, we demonstrate that CD6 and ALCAM form a key adhesive receptor-ligand pair that is not only involved in early DC-T-cell binding but also in sustaining DC-induced T-cell proliferation long after the initial contact has been established.
Zimmerman
Aukje W
AW
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, The Netherlands.
Joosten
Ben
B
Torensma
Ruurd
R
Parnes
Jane R
JR
van Leeuwen
Frank N
FN
Figdor
Carl G
CG
D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005326:Fetal Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013997:Time Factors; D020410:Activated-Leukocyte Cell Adhesion Molecule
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D011993:Recombinant Fusion Proteins; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C062279:CD6 antigen