Validity of the two-signal model for activation of CD28-deficient T lymphocytes: quantitative characterization of an alternative costimulatory function of dendritic cells.
The observation that primary T-dependent immune responses are generated in mice lacking CD28, the only receptor definitively shown to costimulate naive T cells, has led to ambiguity as to whether costimulation is absolutely required for initiation of T-cell responses. In this report, in vitro analysis of the relationship between cell density and proliferation demonstrates that activation of CD28-/- T cells to immobilized T-cell receptor (TCR)-alpha monoclonal antibodies (MoAb) depends on costimulatory signals provided by other cells in culture and occurs only at cell densities sufficient to permit these intercellular interactions. These signals are necessary even under TCR triggering conditions that obviate the CD28 requirement. Dendritic cells (DCs) provide the necessary costimulation in vitro and prime T cells in vivo in CD28-/- mice. Single-cell and limiting dilution analyses indicate that individual T cells from normal and CD28-/- mice produce equivalent interleukin (IL)-2 in response to DCs. However, half as many T cells produce IL-2 when only the CD28-independent pathway is used. Nonetheless, CD28-/- T cells produce sufficient IL-2 to support clonal expansion comparable to that of CD28+/+ T cells, which may account for the equally robust in vivo responses initiated by DCs in normal and CD28-deficient animals.
Cassell
D J
DJ
The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA. djtcassell@aol.com
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D003713:Dendritic Cells / Q000276:immunology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta