Remote T cell co‐stimulation via LFA‐1/ICAM‐1 and CD2/LFA‐3: Demonstration with immobilized ligand/mAb and implication in monocyte‐mediated co‐stimulation

Proliferative response of resting T cells generally requires not only cross‐linking of the T cell receptor (TcR) but also co‐stimulatory signals from accessory molecules. We here have used a “three‐cell” model consisting of: (a) resting human CD4⁺ T cells as responders; (b) CD3 monoclonal antibody (mAb) OKT3 on latex beads as surrogate stimulators; (c) autologous monocytes as source of co‐stimulation. As described by Kawakami et al. (J. Immunol. 1989. 142: 1818), T cell proliferation in this system is observed with paraformaldehyde‐fixed monocytes if they have been activated and interleukin (IL) 1β/IL6 is supplied. Since this three‐cell system provides TcR cross‐linking at a site spatially “remote” from co‐stimulation, they help distinguish adhesion from signal transduction but the molecules that mediate co‐stimulation in this system have not been identified. Our studies now demonstrate that co‐stimulation by the monocytes is dependent on each of two receptor/ligand pathways CD2/LFA‐3 and LFA‐1/ICAM‐1 since it is inhibited by each relevant mAb but not a variety of control mAb. The hypotheses that CD2 and LFA‐1 could each mediate co‐stimulation was tested in simplified model systems in which the monocyte was replaced with immobilized CD2 mAb or purified ICAM‐1 presented on a separate surface from the CD3 mAb. The results in these simplified models demonstrate that on resting T cells either CD2 or LFA‐1 molecules alone can mediate “remote” co‐stimulation unlike most other T cell surface molecules. Co‐stimulation requires IL 1β/IL6 both in the weaker LFA‐1 ligand‐mediated co‐stimulation and at lower CD2 mAb concentrations in the stronger CD2 mAb‐mediated co‐stimulation. Thus: (a) the accessory cell function of stimulated fixed monocytes in T cell proliferation requires both the LFA‐1/ICAM‐1 and CD2/LFA‐3 pathways; and (b) the T cell molecules CD2 and LFA‐1 can give co‐stimulatory signals that can act in a “remote” fashion.