NF-kB subunits in effector T-cell function

NF-κB subunits RelA and c-Rel selectively control CD4⁺ T cell function in multiple sclerosis and cancer

Guilhem Lalle, Raphaëlle Lautraite, Khaled Bouherrou, Maud Plaschka, Aurora Pignata, Allison Voisin, Julie Twardowski, Marlène Perrin-Niquet, Pierre Stéphan, Sarah Durget, Laurie Tonon, Maude Ardin, Cyril Degletagne, Alain Viari, Laurence Belgarbi Dutron, Nathalie Davoust, Thomas S. Postler, Jingyao Zhao, Christophe Caux, Julie Caramel, Stéphane Dalle, Philippe A. Cassier, Ulf Klein, Marc Schmidt-Supprian, Roland Liblau, Sankar Ghosh, Yenkel Grinberg-Bleyer

https://doi.org/10.1084/jem.20231348

The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4⁺ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.