| First Author | Lisiero DN | Year | 2020 |
| Journal | J Immunol | Volume | 205 |
| Issue | 6 | Pages | 1540-1553 |
| PubMed ID | 32817348 | Mgi Jnum | J:301506 |
| Mgi Id | MGI:6502420 | Doi | 10.4049/jimmunol.2000039 |
| Citation | Lisiero DN, et al. (2020) IkappaBalpha Nuclear Export Enables 4-1BB-Induced cRel Activation and IL-2 Production to Promote CD8 T Cell Immunity. J Immunol 205(6):1540-1553 |
| abstractText | Optimal CD8 T cell immunity is orchestrated by signaling events initiated by TCR recognition of peptide Ag in concert with signals from molecules such as CD28 and 4-1BB. The molecular mechanisms underlying the temporal and spatial signaling dynamics in CD8 T cells remain incompletely understood. In this study, we show that stimulation of naive CD8 T cells with agonistic CD3 and CD28 Abs, mimicking TCR and costimulatory signals, coordinately induces 4-1BB and cRel to enable elevated cytosolic cRel:IkappaBalpha complex formation and subsequent 4-1BB-induced IkappaBalpha degradation, sustained cRel activation, heightened IL-2 production and T cell expansion. Nfkbia(NES/NES) CD8 T cells harboring a mutated IkappaBalpha nuclear export sequence abnormally accumulate inactive cRel:IkappaBalpha complexes in the nucleus following stimulation with agonistic anti-CD3 and anti-CD28 Abs, rendering them resistant to 4-1BB induced signaling and a disrupted chain of events necessary for efficient T cell expansion. Consequently, CD8 T cells in Nfkbia(NES/NES) mice poorly expand during viral infection, and this can be overcome by exogenous IL-2 administration. Consistent with cell-based data, adoptive transfer experiments demonstrated that the antiviral CD8 T cell defect in Nfkbia(NES/NES) mice was cell intrinsic. Thus, these results reveal that IkappaBalpha, via its unique nuclear export function, enables, rather than inhibits 4-1BB-induced cRel activation and IL-2 production to facilitate optimal CD8 T cell immunity. |
