|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Heuser, C, Gotot, J, Piotrowski, EChristina, Philipp, M-S, Courrèges, CJohanna Fe, Otte, MSylvester, Guo, L, Schmid-Burgk, JLeo, Hornung, V, Heine, A, Knolle, PAlexander, Garbi, N, Serfling, E, Evaristo, C, Thaiss, F, Kurts, C|
|Date Published||2017 Oct 17|
Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3(+) Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.
|Alternate Journal||Cell Rep|