{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T01:13:22Z","timestamp":1772759602543,"version":"3.50.1"},"reference-count":59,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,2,17]]},"abstract":"<jats:p>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+CD28null T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4+CD28null 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+CD28null T cell clones lacked the expression of KARAP\/DAP12. Despite the absence of KARAP\/DAP12, CD158j was functional and augmented interferon-\u03b3 production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH2-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\u2013regulated 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+CD28null 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+CD28null T cells in RA.<\/jats:p>","DOI":"10.1084\/jem.20020383","type":"journal-article","created":{"date-parts":[[2003,2,18]],"date-time":"2003-02-18T19:28:50Z","timestamp":1045596530000},"page":"437-449","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["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"],"prefix":"10.1084","volume":"197","author":[{"given":"Melissa R.","family":"Snyder","sequence":"first","affiliation":[{"name":"1Departments of Medicine\/Rheumatology and Immunology, Mayo Clinic, Rochester, MN 55905"}]},{"given":"Mathias","family":"Lucas","sequence":"additional","affiliation":[{"name":"2Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Universite\u0301 de la Me\u0301diterrane\u0301e, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France"}]},{"given":"Eric","family":"Vivier","sequence":"additional","affiliation":[{"name":"2Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Universite\u0301 de la Me\u0301diterrane\u0301e, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France"}]},{"given":"Cornelia M.","family":"Weyand","sequence":"additional","affiliation":[{"name":"1Departments of Medicine\/Rheumatology and Immunology, Mayo Clinic, Rochester, MN 55905"}]},{"given":"Jo\u0308rg J.","family":"Goronzy","sequence":"additional","affiliation":[{"name":"1Departments of Medicine\/Rheumatology and Immunology, Mayo Clinic, Rochester, MN 55905"}]}],"member":"291","published-online":{"date-parts":[[2003,2,17]]},"reference":[{"key":"2023072511591058900_BIB1","doi-asserted-by":"crossref","first-page":"14326","DOI":"10.1073\/pnas.95.24.14326","volume":"95","year":"1998","journal-title":"Proc. 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