T cell activation involves the orchestration of several signaling pathways, including that of the 'classical' transcription factor NF-κB components NF-κB1–RelA. The function of the 'nonclassical' NF-κB2–RelB pathway is less clear, although T cells lacking components of this pathway have activation defects. Here we show that mice deficient in NF-κB-inducing kinase have a complex phenotype consisting of immunosuppression mediated by CD25⁻Foxp3⁻ memory CD4⁺ cells and, in the absence of those cells, hyper-responsive naive CD4⁺ T cells, which caused autoimmune lesions after adoptive transfer into hosts deficient in recombination-activating genes. Biochemical studies indicated involvement of a cell-intrinsic mechanism in which NF-κB2 (p100) limits nuclear translocation of NF-κB1–RelA and thereby functions as a regulatory 'brake' for the activation of naive T cells.

NOTE: In the version of this article initially published, the sentence on page 763, column 2, line 12 is incorrect. The correct sentence should end “…and these mice show increased susceptibility to typhlocolitis and infection with Leishmania major but are resistant to experimental autoimmune encephalomyelitis and asthma^14–17.” The error has been corrected in the PDF version of the article.