These experimental observations were then validated in the intact human system by the recent discovery of individuals suffering from profound immune defects [i.e., combined immunodeficiency (CID) and severe combined immunodeficiency (SCID)] involving germline loss-of-function (LOF) mutations in CARD11 (17–19), BCL10 (20), and MALT1 (21–23, 24) (Figure 1). Here, MALT1 is linked to severe combined immunodeficiency.