The identification of a novel T cell activation state controlled by a diabetogenic gene.
The cyclin-dependent kinase inhibitor p27(kip) regulates the cell cycle at the G(1)-S phase restriction point. S phase entry and cell cycle commitment in peripheral T cells requires p27(kip) degradation, normally initiated by the receipt of costimulatory signals such as those provided by B7.1 or IL-2. We have previously reported that T cells from BioBreeding (BB)-diabetes-prone (DP) rats exhibit decreased costimulatory requirements for activation and cell cycle entry. In the present study, we find that peripheral T cell subsets from BB-DP rats demonstrate activation-like characteristics, including significantly reduced levels of p27(kip) as well as increased levels of proliferating cell nuclear Ag (PCNA). Since our previous studies have established that expression of extracellular activation markers are relatively low in unmanipulated peripheral BB-DP T cells; this p27(low) PCNA(high) phenotype represents a novel activation state. Analyses of T cell subsets from congenic rats demonstrate that this phenotype segregates with the lyp diabetogenic locus and that the p27(low) PCNA(high) phenotype is T cell specific. This p27(low) PCNA(high) phenotype is not seen in medullary thymocytes, but appears abruptly in the recent thymic emigrant population, suggesting that the lyp locus does not act directly on cell cycle regulators but rather alters the interaction between T cells and the peripheral environment. These results provide a biochemical basis for costimulation-independent activation and suggest a mechanism whereby a diabetes susceptibility gene contributes to disease development.
Moore
J K
JK
Department of Immunology, Barbara Davis Center for Childhood Diabetes, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Scheinman
R I
RI
Bellgrau
D
D
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D020090:Chromosome Segregation / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D051381:Rats; D011913:Rats, Inbred BB; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018800:Thy-1 Antigens / Q000096:biosynthesis; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D018809:Proliferating Cell Nuclear Antigen; D011948:Receptors, Antigen, T-Cell; D018800:Thy-1 Antigens; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases