IRON DIFFERENTIALLY MODULATES THE CD4-LCK AND CD8-LCK COMPLEXES IN RESTING PERIPHERAL-BLOOD T-LYMPHOCYTES

Clinical and experimental studies performed in situations of iron over load have demonstrated that iron impairs several T-cell functions. We have examined the effect of iron in the form of ferric citrate on the CD4-lck and CD8-lck complexes in view of the key role played by the ty rosine kinase p56lck in regulating T-cell functions. Ferric citrate wa s seen to differentially modulate the CD4-lck and CDS-lck complexes in resting peripheral blood T-lymphocytes (PBLs) cultured in the presenc e of this metal salt for periods of 20 to 24 hr. Thus, whereas ferric citrate invariably induced a marked decrease in the in vitro activity of the CD4-associated lck by three- to fourfold at 100 mu M (P < 3 X 1 0(-5)), it did not affect significantly the in vitro activity of the C D8-associated lck, although modest decreases were observed in some exp eriments. Immunoprecipitation and subsequent lck-immunoblotting reveal ed that the marked decrease in CD4-lck activity induced by 100 mu M of ferric citrate was due to a decrease in the amount of p56lck on CD4 i mmunoprecipitates. Furthermore, flow cytometry analysis showed a decre ase in the surface expression of the CD4 molecule in iron-treated PBLs , as judged by a decrease in the mean fluorescence intensity (MFI), th at was accompanied by a decrease in the percentage of CD4(+) T-lymphoc ytes. In marked contrast, whereas the surface expression of the CD8 mo lecule was slightly decreased, the percentage of CD8(+) T-lymphocytes remained constant. This differential effect of ferric citrate on the C D4(+) and CD8(+) T-cell subsets led to a marked decrease in the CD4/CD 8 ratios in iron-treated PBLs after the 20- to 24-hr period (P < 0.001 ). The present results indicate that iron in the form of ferric citrat e can modulate key molecules involved in the process of T-cell activat ion and therefore influence T-cell-mediated functions. (C) 1995 Academ ic Press, Inc.