T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion

Summary

MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in Lck ^Cre/+ Map3k1 ^f/f mice, and these display larger iNKT cell populations within the liver, spleen, and bone marrow. Mekk1 signaling controls splenic and liver iNKT cell expansion in response to glycolipid antigen. Lck ^Cre/+ Map3k1 ^f/f mice have enhanced liver damage in response to glycolipid antigen. Mekk1 regulates Jnk activation in iNKT cells and binds and transfers Lys63-linked poly-ubiquitin onto Carma1. Map3k1 is critical for the regulation of p27 ^Kip1 (encoded by Cdkn1b).

Graphical Abstract

Highlights

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  iNKT cell expansion is aberrant in Lck ^Cre/+ Map3k1 ^f/f mice

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  Lck ^Cre/+ Map3k1 ^f/f mice have enhanced liver damage in response to glycolipids

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  Mekk1 regulates TCR-dependent Jnk activation

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  Mekk1 regulates p27 ^Kip1 expression to regulate proliferation

Abstract

Suddason et al. use a T-cell-specific deletion of Map3k1 to show that Mekk1 regulates TCR-dependent Jnk activation and Cdkn1b expression to drive proliferation in response to antigen.