IL‐12 plays a pivotal role in LFA‐1‐mediated T cell adhesiveness by up‐regulation of CCR5 expression

The chemokine receptor CCR5 has been implicated in the recruitment of T cells to inflammatory sites. However, the regulation of CCR5 induction on T cells and its contribution to T cell adhesiveness are poorly understood. Using a Th1 clone, 2D6, that can be maintained with interleukin (IL)‐12 or IL‐2 alone (designated 2D6IL‐12 or 2D6IL‐2, respectively), we investigated how CCR5 is induced on T cells and whether CCR5 is responsible for up‐regulating the function of adhesion molecules. 2D6IL‐12 grew, forming cell aggregates, in culture containing IL‐12. This was due to lymphocyte function‐associated antigen (LFA)‐1–intercellular adhesion molecule (ICAM)‐1 interaction, because 2D6IL‐12 expressed both LFA‐1 and ICAM‐1 and cell aggregation was inhibited by anti‐ICAM‐1 monoclonal antibody. Despite comparable levels of LFA‐1 and ICAM‐1 expression, 2D6IL‐2 cells did not aggregate in culture with IL‐2. It is important that there was a critical difference in CCR5 expression between 2D6IL‐12 and 2D6IL‐2; the former expressed high levels of CCR5, and the latter expressed only marginal levels. Both types of cells expressed detectable albeit low levels of RANTES (regulated on activation, normal T expressed and secreted) mRNA. Unlike IL‐12 or IL‐2, IL‐18 induced high levels of RANTES mRNA expression without modulating CCR5 expression. Therefore, combined stimulation with IL‐12 and IL‐18 strikingly up‐regulated 2D6 cell aggregation. Notably, LFA‐1‐mediated aggregation of 2D6IL‐12 cells was suppressed by anti‐CCR5 antibody. These results indicate that IL‐12 plays a critical role in CCR5 expression on Th1 cells and consequently contributes to CCR5‐mediated activation of LFA‐1 molecules.