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*
Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and
Howard Hughes Medical Institute and Rockefeller University, New York, NY 10021
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-
, 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- 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.
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