Immune System Dysfunction and Autoimmune Disease in Mice Lacking Emk (Par-1) Protein Kinase

Abstract

Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption.Emk^−/− mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4⁺T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. AsEmk^−/− animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.

ACKNOWLEDGMENTS

We thank E. Unanue for help with the electron microscopy and data analysis. T. McDonnell and M. Zutter are thanked for their interpretation of tissue histology. O. Kanagawa and K Sabelko are thanked for assistance with early characterization of the immune cell phenotypes. M. LaRegina is thanked for providing pathology services, M. Dustin is thanked for help with the chemotaxis assays, and R. Schreiber is thanked for assistance with the ELISAs. A. Shaw, D. Chaplin, T. Chatilla, J. Atkinson, G. Longmore, and P. Allen are thanked for valuable discussions and input. T. Ley and members of the Division of Bone Marrow Transplantation and Stem Cell Biology at Washington University are thanked for their helpful suggestions on phenotype analysis. We thank the Siteman Cancer Center ES stem cell core at Washington University for performing the ES cell electroporations, and we thank M. White for mouse blastocyst injections and generation of chimeric mice.

This work was supported in part by a scholarship to J.H. from the Lucille P. Markey foundation. A.C.C., K.M.M., and H.P.-W. are Investigators of the Howard Hughes Medical Institute.