A Na(+)-dependent Ca2+ exchanger generates the sustained increase in intracellular Ca2+ required for T cell activation.
Movement of extracellular Ca2+ is required for the sustained increase in [Ca2+]i necessary for T cell activation. However, the mechanisms mediating mitogen-stimulated Ca2+ movement into T cells have not been completely delineated. To explore the possibility that a Na(+)-dependent Ca2+ (Na+/Ca2+) exchanger might play a role in the mitogen-induced increases in [Ca2+]i required for T cell activation, the effects of inhibitors of this exchanger were examined. Inhibitors of Na+/Ca2+ exchange suppressed the sustained increase in [Ca2+]i stimulated by ligation of the CD3-TCR complex, but did not affect mobilization of intracellular Ca2+ stores. Consistent with the importance of this prolonged increase in [Ca2+]i in T cell activation, Na+/Ca2+ exchange inhibitors, but not inhibitors of the Na+/H+ antiporter, inhibited DNA synthesis stimulated by immobilized anti-CD3 mAb. Inhibition only occurred when the agents were present during the first hours after stimulation. These agents also inhibited IL-2 production, but not expression of the IL-2R or of an early activation Ag, 4F2. Inhibition of IL-2 production did not account for the inhibition of T cell proliferation as addition of exogenous IL-2 or phorbol ester (PDB) did not overcome the inhibition. In contrast, activation pathways that are not thought to require an increase in [Ca2+]i such as IL-1 + PDB or engagement of CD28 in the presence of PDB were less sensitive to the suppressive effects of inhibitors of Na+/Ca2+ exchange. Thus, proliferation induced by these stimuli was not suppressed by low concentrations of these inhibitors and IL-2 production induced by mAb to CD28 + PDB was not inhibited by any concentration of inhibitors of Na+/Ca2+ exchange. These results suggest that stimulation of a Ca2+ transporter with the same spectrum of inhibition as the Na+/Ca2+ exchanger in other tissues mediates the sustained increase in [Ca2+]i required for T cell activation after CD3 ligation.
Wacholtz
M C
MC
Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
Cragoe
E J
EJ
Lipsky
P E
PE
D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D001693:Biological Transport, Active / Q000187:drug effects; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015290:Second Messenger Systems; D015398:Signal Transduction; D012964:Sodium / Q000502:physiology*; D019831:Sodium-Calcium Exchanger; D013601:T-Lymphocytes / Q000502:physiology*
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D002352:Carrier Proteins; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium