Signaling pathways activated by leukocyte function-associated Ag-1-dependent costimulation

LFA-1 binding to ICAM-1 can enhance TCR-dependent proliferation of T cells, but it has been difficult to distinguish contributions from increased adhe sion, and thus TCR occupancy, versus costimulatory signaling. Whether LFA-1 ligation results in generation of a unique costimulatory signal(s) distinc t from those activated by the TCR has been unclear. Using purified ligands, it is shown that ICAM-1 and B7.1 provide comparable costimulation for prol iferation of CD8(+) T cells, and that both ligands up-regulate the activiti es of phosphatidylinositol 3-kinase, sphingomyelinase, and c-Jun NH2-termin al kinase (JNK). These pathways are distinct from those activated by the TC R, and have previously been implicated in up-regulating IL-2 production in response to CD28-B7 interaction. Thus, under conditions in which ICAM-1 pro vides costimulation of proliferation, LFA-1 ligation activates some of the same signaling pathways as does CD28 ligation. LFA-I and CD28 do not act id entically, however, as indicated by differential sensitivity to inhibitors of phosphatidylinositol 3-kinase; LFA-1-dependent costimulation of prolifer ation is inhibited, while CD28-dependent costimulation is not. Given the br oad distribution of class I and ICAMs on many cell types, the ability of LF A-1 to provide costimulatory signals has implications for where and how CD8 (+)CTL may become activated in response to an antigenic challenge.