Signaling alterations in activation-induced nonresponsive CD8 T cells

Costimulation-dependent production and autocrine use of IL-2 by activated C D8 T cells results in initial clonal expansion, but this is transient. The cells quickly become anergic, unable to produce IL-2 in response to Ag and costimulation, irrespective of the form of costimulation. This activation-i nduced non-responsiveness (AINR) differs from "classical" anergy in that it results despite the cells receiving both signal 1 and signal 2. AINR cells can still proliferate in response to exogenous IL-2, but can no longer pro duce it. Other TCR-mediated events including cytolytic function and IFN-gam ma production are not affected in the AINR state. To characterize the mecha nism(s) responsible for lack of IL-2 production in CD8 T cells in the AINR state, microspheres bearing immobilized anti-TCR Abs or peptide-MHC complex es, B7-1, and ICAM-1 were used to provide well-defined stimuli to the cells . Comparison of normal and AINR cells revealed that in AINR cells extracell ular signal-regulated kinase (ERK) is upregulated more transiently, Janus k inase activation is substantially reduced, and activation of p38 is elimina ted. PMA and ionomycin restored proliferation and IL-2 production in AINR c ells, indicating a signaling defect upstream of Ras and protein kinase C. I nhibitors of ERK (PD98059) and of p38 kinase (SB202190) blocked IL-2 mRNA e xpression and proliferation of both peptide-MHC/B7- 1/ICAM-1-stimulated nor mal cells and PMA/ionomycin-stimulated AINR cells. Together these results d emonstrate that activation of at least ERK and p38 is essential for IL-2 pr oduction by CD8 T cells and that up-regulation of these mitogen-activated p rotein kinases, along with Janus kinase, is defective in AINR cells. The Jo urnal of Immunology, 2001.