CD63 as an activation-linked T cell costimulatory element.
Dendritic cells (DC) are unique in their capacity to either stimulate or regulate T cells, and receptor/ligand pairs on DC and T cells are critically involved in this process. In this study we present such a molecule, which was discovered by us when analyzing the functional effects of an anti-DC mAb. This mAb, 11C9, reacted strongly with DC, but only minimally with lymphocytes. In MLR it constantly reduced DC-induced T cell activation. Therefore, we assumed that mAb 11C9 primarily exerts its functions by binding to a DC-structure. This does not seem to be the case, however. Preincubation of DC with mAb 11C9 before adding T cells had no inhibitory effect on T cell responses. Retroviral expression cloning identified the 11C9 Ag as CD63. This lysosomal-associated membrane protein (LAMP-3), is only minimally expressed on resting T cells but can, as we show, quickly shift to the surface upon stimulation. Cross-linkage of that structure together with TCR-triggering induces strong T cell activation. CD63 on T cells thus represents an alternative target for mAb 11C9 with its binding to activated T cells rather than DC being responsible for the observed functional effects. This efficient CD63-mediated costimulation of T cells is characterized by pronounced induction of proliferation, strong IL-2 production and compared with CD28 enhanced T cell responsiveness to restimulation. Particularly in this latter quality CD63 clearly surpasses several other CD28-independent costimulatory pathways previously described. CD63 thus represents an activation-induced reinforcing element, whose triggering promotes sustained and efficient T cell activation and expansion.
Pfistershammer
Katharina
K
Institute of Immunology, Medical University of Vienna, Borschkegasse 8A, A-1090 Vienna, Austria.
Majdic
Otto
O
Stöckl
Johannes
J
Zlabinger
Gerhard
G
Kirchberger
Stefanie
S
Steinberger
Peter
P
Knapp
Walter
W
D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D060149:Tetraspanin 30
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C554586:CD63 protein, human; C554587:Cd63 protein, mouse; D003432:Cross-Linking Reagents; D007155:Immunologic Factors; D007376:Interleukin-2; D010980:Platelet Membrane Glycoproteins; D060149:Tetraspanin 30