Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells.
Activation of CD4(+) T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4(+)CD28(null) T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4(+)CD28(null) T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-gamma production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4(+)CD28(null) T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA.
Snyder
Melissa R
MR
Department of Medicine/Rheumatology and Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Lucas
Mathias
M
Vivier
Eric
E
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D054340:Receptors, KIR; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; C120528:HCST protein, human; D008565:Membrane Proteins; D016755:Proto-Oncogene Proteins c-jun; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D054340:Receptors, KIR; C110546:TYROBP protein, human; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases