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Signaling Pathways Activated by Leukocyte Function-Associated Ag-1-Dependent Costimulation¹

Hsiao-Tzu Ni^*, Matthew J. Deeths^*, Wei Li, Daniel L. Mueller and Matthew F. Mescher^2,*

^* Department of Laboratory Medicine and Pathology, and Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455

LFA-1 binding to ICAM-1 can enhance TCR-dependent proliferation of T cells, but it has been difficult to distinguish contributions from increased adhesion, and thus TCR occupancy, versus costimulatory signaling. Whether LFA-1 ligation results in generation of a unique costimulatory signal(s) distinct 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 proliferation of CD8⁺ T cells, and that both ligands up-regulate the activities of phosphatidylinositol 3-kinase, sphingomyelinase, and c-Jun NH₂-terminal kinase (JNK). These pathways are distinct from those activated by the TCR, and have previously been implicated in up-regulating IL-2 production in response to CD28-B7 interaction. Thus, under conditions in which ICAM-1 provides costimulation of proliferation, LFA-1 ligation activates some of the same signaling pathways as does CD28 ligation. LFA-1 and CD28 do not act identically, however, as indicated by differential sensitivity to inhibitors of phosphatidylinositol 3-kinase; LFA-1-dependent costimulation of proliferation is inhibited, while CD28-dependent costimulation is not. Given the broad distribution of class I and ICAMs on many cell types, the ability of LFA-1 to provide costimulatory signals has implications for where and how CD8⁺CTL may become activated in response to an antigenic challenge.