Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response.
4-1BB is a costimulatory member of the TNFR family, expressed on activated CD4(+) and CD8(+) T cells. Previous results showed that 4-1BB-mediated T cell costimulation is CD28-independent and involves recruitment of TNFR-associated factor 2 (TRAF2) and activation of the stress-activated protein kinase cascade. Here we describe a role for the p38 mitogen-activated protein kinase (MAPK) pathway in 4-1BB signaling. Aggregation of 4-1BB alone induces p38 activation in a T cell hybridoma, whereas, in normal T cells, p38 MAPK is activated synergistically by immobilized anti-CD3 plus immobilized 4-1BB ligand. 4-1BB-induced p38 MAPK activation is inhibited by the p38-specific inhibitor SB203580 in both a T cell hybridoma and in murine T cells. T cells from TRAF2 dominant-negative mice are impaired in 4-1BB-mediated p38 MAPK activation. A link between TRAF2 and the p38 cascade is provided by the MAPK kinase kinase, apoptosis-signal-regulating kinase 1. A T cell hybrid transfected with a kinase-dead apoptosis-signal-regulating kinase 1 fails to activate p38 MAPK in response to 4-1BB signaling. To assess the role of p38 activation in an immune response, T cells were stimulated in an MLR in the presence of SB203580. In a primary MLR, SB203580 blocked IL-2, IFN-gamma, and IL-4 secretion whether the costimulatory signal was delivered via 4-1BB or CD28. In contrast, following differentiation into Th1 or Th2 cells, p38 inhibition blocked IL-2 and IFN-gamma without affecting IL-4 secretion. Nevertheless, IL-4 secretion by Th2 cells remained costimulation-dependent. Thus, critical T cell signaling events diverge following Th1 vs Th2 differentiation.
Cannons
J L
JL
Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Howard Hughes Medical Institute and Rockefeller University, New York, NY 10021, USA.
Choi
Y
Y
Watts
T H
TH
D000818:Animals; D015703:Antigens, CD; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D006825:Hybridomas; D008024:Ligands; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D016207:Cytokines; D008024:Ligands; D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases