Loss of a gimap/ian gene leads to activation of NF-kappaB through a MAPK-dependent pathway.
The diabetes-prone biobreeding (BB-DP) rat contains the lyp mutation which results in lymphopenia and promotes the progression of a T cell-mediated autoimmune attack of the pancreas in certain rat strains. This mutation has been mapped to a gene which bears homology to human Gimap5/Ian5 and results in the truncation and loss of activity of this protein. The lymphopenic state induced by the loss of this protein has led to the proposal that Gimap5 has an anti-apoptotic function. Previously we described an additional phenotype of incomplete activation mediated by the loss of Gimap5 function. Here we further characterize this incomplete activation phenotype and map a potential signal transduction pathway leading to activation. We show that CD5 expression on peripheral T cells is elevated in Gimap5 animals, while thymocyte expression remains similar between the two strains. Additionally, we show that NF-kappaB but not NFAT is activated in unstimulated Gimap5 mutant T cells as compared to unstimulated wild type T cells. Mapping this activation to its upstream source we show that activation of NF-kappaB is correlated with an activation of IKK. Using a variety of kinase inhibitors we further map this increase in IKK to an increase in MEK activation. Finally, to counter the possibility that activation is an indirect consequence of the lymphopenic environment, we created bone marrow chimeras in which Gimap5 mutant T cells developed in a normal environment and show that these cells retain their activated phenotype. Together, we interpret these data as demonstrating that the activation caused by loss of Gimap5 is a cell intrinsic phenomenon caused, in part, by a MEK-dependent activation of IKK. This, in turn, would suggest that Gimap5 functions to promote both T cell survival and quiescence and that these pathways are biochemically linked.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
Rene
R
Kupfer
Julie
J
Lang
Cheryll
C
Williams-Skipp
Matt
M
Nelson
Donald
D
Bellgrau
Robert I
RI
Scheinman
D000818:Animals; D018956:CD5 Antigens / Q000096:biosynthesis / Q000276:immunology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D020935:MAP Kinase Signaling System / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D018956:CD5 Antigens; D016328:NF-kappa B; D019204:GTP-Binding Proteins; C494977:Gimap5 protein, rat