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Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response.
J Immunol. 2000 Dec 01; 165(11):6193-204.JI

Abstract

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.

Authors+Show Affiliations

Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Howard Hughes Medical Institute and Rockefeller University, New York, NY 10021, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11086053

Citation

Cannons, J L., et al. "Role of TNF Receptor-associated Factor 2 and P38 Mitogen-activated Protein Kinase Activation During 4-1BB-dependent Immune Response." Journal of Immunology (Baltimore, Md. : 1950), vol. 165, no. 11, 2000, pp. 6193-204.
Cannons JL, Choi Y, Watts TH. Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. J Immunol. 2000;165(11):6193-204.
Cannons, J. L., Choi, Y., & Watts, T. H. (2000). Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. Journal of Immunology (Baltimore, Md. : 1950), 165(11), 6193-204.
Cannons JL, Choi Y, Watts TH. Role of TNF Receptor-associated Factor 2 and P38 Mitogen-activated Protein Kinase Activation During 4-1BB-dependent Immune Response. J Immunol. 2000 Dec 1;165(11):6193-204. PubMed PMID: 11086053.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. AU - Cannons,J L, AU - Choi,Y, AU - Watts,T H, PY - 2000/11/22/pubmed PY - 2001/2/28/medline PY - 2000/11/22/entrez SP - 6193 EP - 204 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 165 IS - 11 N2 - 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. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/11086053/Role_of_TNF_receptor_associated_factor_2_and_p38_mitogen_activated_protein_kinase_activation_during_4_1BB_dependent_immune_response_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=11086053 DB - PRIME DP - Unbound Medicine ER -