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 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.
Ni
H T
HT
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis 55455, USA.
Deeths
M J
MJ
Li
W
W
Mueller
D L
DL
Mescher
M F
MF
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D018122:B7-1 Antigen / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000276:immunology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D000077191:Wortmannin
D000730:Androstadienes; D018122:B7-1 Antigen; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018799:Intercellular Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D016169:Lymphocyte Function-Associated Antigen-1; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013108:Sphingomyelin Phosphodiesterase; D000077191:Wortmannin