Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation.
TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1(nuc)) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1(nuc) T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1(nuc) T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1(nuc) destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines.
Pan
Minggui
M
Division of Oncology, Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA. minggui.pan@kp.org
Winslow
Monte M
MM
Chen
Lei
L
Kuo
Ann
A
Felsher
Dean
D
Crabtree
Gerald R
GR
D021581:Active Transport, Cell Nucleus; D000409:Alanine / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000276:immunology; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D018106:CD28 Antigens; D016207:Cytokines; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D012694:Serine; D016572:Cyclosporine; D038362:Glycogen Synthase Kinase 3; D000409:Alanine