NF-?B transcription factors RelA and c-Rel selectively control CD4+ T-cell function in multiple sclerosis and cancer [bulk_mouse]

The outcome of cancer and autoimmunity is dictated by the recruitment and effector functions of CD4+ conventional T cells (Tconv cells). The NF-kappaB (NF-?B) family of transcription factors is implicated in different aspects of Tconv cell biology, but the cell-autonomous roles of NF-?B subunits are elusive. Here, we explored the contributions of canonical RelA and c-Rel subunits to Tconv function in health and disease. We found that RelA, rather than c-Rel, shaped the transcriptome of mouse and human Tconv cells at steady-state and was required for Tconv polarization toward the TH17 lineage in vitro. RelA-deficient mice were fully protected against neuro-inflammation in a mouse model of multiple sclerosis (MS), because of defective transition to a pathogenic TH17 gene expression program. In contrast, Tconv-restricted ablation of c-Rel, but not RelA, impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. c-Rel in Tconv cells was required for the response to PD-1-blockade therapy, and a c-Rel-dependent gene signature was correlated with better response and prognosis in anti-PD-1-treated patients. Our data demonstrate a division of labor between different subunits of the NF-?B pathway, paving the way for subunit-targeted immunotherapies. Overall design: CD4+CD25- Tconv cells were isolated from spleen and LNs of control and cKO mice, and stimulated with anti-CD3/CD28 and IL-2 for 4 hours. Cells were then subjected to bulk RNAseq