Regulation of expression of interleukin 2 receptors upon triggering of the TCR-CD3 complex on human T lymphocytes.
Monoclonal antibodies reactive with CD3 molecular complex can induce antigen-associated early biochemical changes in purified, monocyte-depleted resting T cell populations and synergize with interleukin 2 (IL2) in the induction of T-cell proliferation. Interleukin 2 mediates its effects via two receptor molecules of apparent 70-75 kD (p70/p75) and 50-55 kD (p50/55) molecular weights respectively. Using radioactive IL2 and bi-functional cross-linking chemistry, we are able to determine that incubation of purified, monocyte-depleted, resting T cells with anti-CD3 (OKT3) antibody induces a significant and selective increase in the expression of p70/75 IL2 receptors from their low constitutively expressed levels. This event occurs in the complete absence of cellular proliferation. Although IL2 also causes the upregulation of p70/75 molecules, it is the synergistic action of both antibody and lymphokine which is needed for the induction of significant amounts of the p50/55 IL2 receptors and the concomitant cellular proliferation. The effect of anti-CD3 on p70/75 receptor expression is specific, as determined by the inability of a non-related (anti-CD2) monoclonal antibody of the same subclass (IgG2a) to induce a similar effect. The Ca++ ionophore ionomycin, under conditions that cause significant intracellular Ca++ influx cannot by itself mediate upregulation of IL2 receptor expression in T cells. Since anti-CD3 itself can induce intracellular Ca++ increase in purified T cells, the finding with the ionophore suggests that the intracellular Ca++ accumulation alone cannot account for the IL2 receptor molecular events described here. Addition of PMA induces both p70/75 and p50/55 IL2 receptor upregulation, as well as IL2-dependent proliferation. Although resting T cells constitutively express p70/75 receptors, under our experimental conditions and with the concentration of IL2 used, these molecules cannot transduce the lymphokine signal efficiently. Thus, in a physiologic context, a simple interpretation of our data could be that upon interaction of the TCR/CD3 with antigen a selective upregulation of p70/75 IL2 receptors renders them competent of not only binding the lymphokine, but also transducing its signal. The latter event leads to the expression of p50/55 receptors and subsequent proliferation. Whether an increase in the numbers of these receptors is all that is needed or additional events are necessary merits further investigation.
Kabouridis
P S
PS
Department of Biology, San Diego State University, California 92182.
Tsoukas
C D
CD
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium