An accessory cell-derived costimulatory signal acts independently of protein kinase C activation to allow T cell proliferation and prevent the induction of unresponsiveness.
Presentation of Ag to type I CD4+ T cell clones by chemically fixed APC results in the induction of a long-lasting state of proliferative unresponsiveness in the T cell. Ag-specific TCR interactions do occur during this stimulation, as Ag- and Ia molecule-dependent increases in intracellular calcium free ion concentration can be demonstrated, yet free inositol phosphate generation is low and neither IL-2 synthesis nor proliferation occur. The addition of normal allogeneic accessory cells during this stimulation can restore the T cell proliferative response, as well as prevent the induction of unresponsiveness, thus defining an accessory cell-dependent costimulatory activity necessary for proliferation. We have now examined the biochemical effects of this costimulatory activity on early T cell activation. Normal accessory cell costimulatory activity was found to be incapable of augmenting the generation of free inositol phosphate in response to either fixed APC plus Ag or Con A alone. Furthermore, protein kinase C-dependent CD3 gamma-chain phosphorylation occurred in response to either fixed APC plus Ag or Con A alone, and the addition of normal accessory cells had no effect on the level of this phosphorylation. Finally, minimal CD3 zeta-chain tyrosine phosphorylation occurred during the induction of unresponsiveness with Ag and fixed APC alone and this also was not affected by the costimulatory activity. Our results demonstrate that T cell Ag receptor-mediated increases in intracellular calcium free ion concentration and protein kinase C activation occur independently of an accessory cell-derived costimulatory signal. In the absence of this costimulatory signal, these two intracellular second messengers are insufficient to induce a maximal proliferative response and in fact lead to a state of unresponsiveness.
Mueller
D L
DL
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Jenkins
M K
MK
Schwartz
R H
RH
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017252:CD3 Complex; D003208:Concanavalin A / Q000494:pharmacology; D004075:Diglycerides / Q000096:biosynthesis; D004789:Enzyme Activation; D007295:Inositol Phosphates / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011493:Protein Kinase C / Q000032:analysis*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D004075:Diglycerides; D007295:Inositol Phosphates; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D003208:Concanavalin A; D011493:Protein Kinase C