Genetic insights into Map3k-dependent proliferative expansion of T cells

Mapks are important regulators of T cell proliferative expansion and cell cycle progression. Detailed genetic analysis of unconventional iNKT cells in both Map3k1^ΔKD and Lck^Cre/+Map3k1^f/f mice demonstrated that Mekk1 (encoded by Map3k1) signaling activates Mapks to regulate Cdkn1b (encoding p27^Kip1) expression and p27^Kip1-dependent proliferative expansion in response to antigen. Mekk1 signaling and activation of E3 ubiquitin ligase Itch, by a phosphorylation-dependent conformational change, is also an important regulatory mechanism for the control of T helper cell cytokine production. Cdkn1b expression is regulated by Mekk1-dependent signaling in differentiated Th17 cells. Mekk1 is one of the 19 Ste11-like Map3ks, and Mekk1 signaling regulates iNKT cell proliferative expansion in response to glycolipid antigens and T cell homeostasis in the liver. Tak1 (encoded by Map3k7), a related Map3k to Mekk1, similarly regulates the proliferative expansion and homeostasis of T cells in the liver, and this illustrates the importance of multiple Map3ks for mammalian Mapk signaling.