Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc

Ann M. Ranger, Harvard School of Public Health
Martin R. Hodge, Harvard School of Public Health
Ellen M. Gravallese, University of Massachusetts Medical School
Mohammed Oukka, Harvard School of Public Health
Laurie Davidson, Howard Hughes Medical Institute
Frederick W. Alt, Howard Hughes Medical Institute
Fabienne C. de la Brousse, Tularik, Inc.
Timothy Hoey, Tularik, Inc.
Michael Grusby, Harvard School of Public Health
Laurie H. Glimcher, Harvard School of Public Health

At the time of publication, Ellen Gravallese was not yet affiliated with the University of Massachusetts Medical School.

Abstract

The NF-AT family of transcription factors activates early immune response genes such as cytokines. In the adult, NF-ATc is expressed exclusively in the lymphoid system and is induced upon lymphocyte activation. NF-ATc null mutant mice die in utero of cardiac failure, precluding analysis of the role of NF-ATc in lymphocyte activation. By using RAG-2-deficient blastocyst complementation, we now demonstrate that young, highly chimeric mice lacking NF-ATc have impaired repopulation of both thymus and peripheral lymphoid organs. Furthermore, NF-ATc deficiency impaired T lymphocyte activation and secretion of IL-4. B lymphocytes displayed reduced proliferation and a selective loss of IL-4-driven immunoglobulin isotypes both in vivo and in vitro. Our data demonstrate that NF-ATc is essential for the optimal generation and function of mature T and B lineage cells, with an especially profound effect on IL-4-driven responses.