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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

Melissa R. Snyder¹, Mathias Lucas², Eric Vivier², Cornelia M. Weyand¹ and Jörg J. Goronzy¹

¹ Departments of Medicine/Rheumatology and Immunology, Mayo Clinic, Rochester, MN 55905
² Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Université de la Méditerranée, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France

Address correspondence to Jörg J. Goronzy, 401 Guggenheim, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Phone: 507-284-1650; Fax: 507-284-5045; E-mail: goronzy.jorg{at}mayo.edu

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- 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–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.

Key Words: autoimmunity • pathogenesis • rheumatoid arthritis • costimulation • killer immunoglobulin-like

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