Quantitative interplay between activating and pro-apoptotic signals dictates T cell responses.
Antigen-presenting cells (APC) can express surface ligands with both T cell activating and inhibitory capacities, prompting the question of how responding T cells integrate opposing trans signals concurrently delivered by APC. To address this question in a quantitative fashion, we turned to protein transfer as a unique experimental approach that is well-suited for addressing such questions from a quantitative standpoint. Costimulatory (either B7-1*Fc(gamma1) or Fc(gamma1)*4-1BBL) and pro-apoptotic (Fc(gamma1)*FasL) Fc fusion proteins were quantitatively "painted" in varying ratios onto surrogate APC pre-coated with palmitated-protein A, the latter serving as a surface anchor. Evaluating the signaling potential of these various painted cells in a standard in vitro T cell proliferation assay, we demonstrated that at a given level of TCR triggering, the quantitative balance between costimulator (B7-1 or 4-1BBL) and FasL dictates the magnitude of the proliferative T cell response. Furthermore, when the costimulator density is kept constant, there is also a quantitative balance between TCR-directed and FasL signals. Interesting species-specific nai;ve versus memory T cell subset differences emerged with regard to susceptibility to Fas-mediated apoptosis and costimulator:FasL opposition. Taken together, these data demonstrate for the first time a quantitative interplay between activating and pro-apoptotic trans signals that dictates the magnitude of T cell responses.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 6 Gates Building, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
Aoshuang
A
Chen
Guoxing
G
Zheng
Mark L
ML
Tykocinski
D053330:4-1BB Ligand; D000938:Antigen-Presenting Cells / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013205:Staphylococcal Protein A / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D053330:4-1BB Ligand; D018122:B7-1 Antigen; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D013205:Staphylococcal Protein A; C505974:TNFSF9 protein, human; D014409:Tumor Necrosis Factor-alpha