Dominique N. Lisiero, Zhang Cheng, Melba M. Tejera, Brandon T. Neldner, Jay W. Warrick, Shelly M. Wuerzberger-Davis, Alexander Hoffmann, M. Suresh and Shigeki Miyamoto
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:IκBα complex formation and subsequent 4-1BB–induced IκBα degradation, sustained cRel activation, heightened IL-2 production and T cell expansion. NfkbiaNES/NES CD8 T cells harboring a mutated IκBα nuclear export sequence abnormally accumulate inactive cRel:IκBα 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 NfkbiaNES/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 NfkbiaNES/NES mice was cell intrinsic. Thus, these results reveal that IκBα, 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.
Dominique N. L., Zhang C., Melba M. T. et al. IκBα Nuclear Export Enables 4-1BB–Induced cRel Activation and IL-2 Production to Promote CD8 T Cell Immunity. J Immunol September 15, 2020, 205 (6) 1540-1553; DOI: https://doi.org/10.4049/jimmunol.2000039
The following Bio X Cell in vivo monoclonal antibodies were featured in the publication:
- InVivoMAb anti-mouse CD3 (Clone 17A2, Bio X Cell catalog no. BE0002)
- InVivoMAb anti-mouse CD28 (Clone 37.51, Bio X Cell catalog no. BE0015-1)
- anti-mouse 4-1BB (CD137) (Clone 3H3, Bio X Cell catalog no. BP0239; BE0239)
- anti-mouse OX40 (CD134) (Clone OX-86, Bio X Cell catalog no. BP0031; BE0031)