Proteolysis of NF-κB1 p105 is essential for T cell antigen receptor-induced proliferation

The functional importance of TCR-induced degradation of p105 NF-κB is unclear. Ley and colleagues now show it is required for regulatory and memory T cell differentiation and for mature T cell function. To investigate the importance of proteolysis of NF-κB1 p105 induced by the kinase IKK in activation of the transcription factor NF-κB, we generated ' Nfkb1 SSAA/SSAA ' mice, in which the IKK-target serine residues of p105 were substituted with alanine. Nfkb1 SSAA/SSAA mice had far fewer CD4 + regulatory and memory T cells because of cell-autonomous defects. These T cell subtypes require activation of NF-κB by the T cell antigen receptor for their generation, and the Nfkb1 SSAA mutation resulted in less activation of NF-κB in CD4 + T cells and proliferation of CD4 + T cells after stimulation of the T cell antigen receptor. The Nfkb1 SSAA mutation also blocked the ability of CD4 + T cells to provide help to wild-type B cells during a primary antibody response. IKK-induced p105 proteolysis is therefore essential for optimal T cell antigen receptor–induced activation of NF-κB and mature CD4 + T cell function.