particular, it will be important to study pancreata from long-term diabetic subjects with documented C-peptide secretion(not available for these subjects).

doi:10.1016/j.clim.2007.03.237

F.25 Regulation of Pathogenicity Through CD40Expressed on CD4 T CellsRocky Baker, Postdoctoral Fellow, Department ofImmunology, University of Colorado Health Sciences Center,Denver, CO, David Wagner, Assistant Professor, Departmentof Immunology, University of Colorado Health SciencesCenter, Denver, CO, Kathryn Haskins, Professor, NJMRC,Denver, CO

We have reported previously that the costimulatorymolecule CD40 is a marker of autoreactive T cells found ondiabetogenic T cell clones and that CD40+ T cells from theNOD mouse transfer diabetes. Although there is strongevidence that CD40 is functional on T cells, CD40 expressionon Tcells remains controversial because of typically low andvariable levels of CD40 on primary T cells. We haveinvestigated the conditions under which T cells express theCD40 molecule and how CD40 expression contributes topathogenicity of autoreactive T cells. First, we havedemonstrated that CD40 levels on primary T cells can beinduced on 90% of CD4+CD40− T cells from NOD mice uponactivation. Furthermore, comparing naive and primed Tcellsfrom different TCR-Tg NOD mouse models, we have foundthat the ability to express CD40 depends on the activationstatus of the T cell. Second, we investigated how CD40costimulation influences the effector function of CD4 T cellsby comparing CD28 and CD40 costimulation in NOD mice. Wehave found that CD40 engagement can replace or synergizewith CD28 costimulation in terms of T cell activation andproliferation. However, there is a major difference whencostimulation occurs through CD40: our results indicate thatCD40 costimulation influences the Th1/Th2 balance differ-ently and that CD40 engagement on autoreactive T cellsenhances a Th1 effector phenotype. Taken together, the dataindicate that CD40 is an effective alternative pathway toCD28 costimulation and might regulate the pathogenicity ofCD4 T cells in T1D.

doi:10.1016/j.clim.2007.03.238

F.26 TRECS and Telomerase Analysis of Lymphocytesfrom Autoimmune Thyroid Disease Patients Point tothe Migration of Recent Thymic Emigrants to theThyroid Gland at the First Stages of DiseaseRicardo Pujol Borrell, Professor, Blood and Tissue Bank(LIRAD), Health Science Research Institut, Badalona, MarcoAntonio Fernandez, Head Cytometry Facility, Health ScienceResearch Institut, Badalona, Maria Pilar Armengol,Posdoctoral Fellow, Blood and Tissue Bank (LIRAD), HealthScience Research Institut, Badalona, Manel Juan, Head HLALaboratory, Blood and Tissue Bank (LIRAD), Health ScienceResearch Institut, Badalona, Lidia Sabater, Research Fellow,

Blood and Tissue Bank (LIRAD), Health Science ResearchInstitut, Badalona, Ricardo Pujol Borrell, Head ImmunologyLaboratory, Blood and Tissue Bank (LIRAD), Health ScienceResearch Institut, Badalona

According to the threshold hypothesis of autoimmunity,the abundance and affinity of autoreactive T cells in therepertoire determine the probability for the triggering ofautoimmune diseases. We have investigated how recentthymic emigrants may contribute the autoreactive repertoirein autoimmune thyroid disease (AITD) patients, by measuringTRECs in PBLs from AITD patients (n=50) and controls (n=55)and in intrathyroidal lymphocytes from autoimmune thyroidglands. TRECS were higher in AITD patients, especially in theN45-year-old patients. The analysis of TRECS in intrathyroidallymphocytes (ITL) (n=45) in relation to disease durationrevealed a distinct pattern of distribution: TRECSwere higherin ITL than in PBL in b30-month-disease-duration patients(fourfold excess in average), and vice-versa N30-monthpatients (tenfold excess). Interestingly there was a correla-tion between the levels of TRECS in ITLs and PBLs in bothgroups but of different sign and intensity: it was stronger inthe N30 months (r=0.94) than in the b30 months (r=0.535).This may indicate that while in the N30 months group theTRECs in ITLs is dependent on the TRECs in PBLs, this is not thecase in the b30 months. The study of the telomere length didnot reveal a relation between TRECs and telomere length inthe T cells but was significantly shorter in ITLs cells than inPBLs. These results suggest that early in disease there is amigration to AITD glands of T lymphocytes newly generated inthe thymus that then undergoes a local expansion.

doi:10.1016/j.clim.2007.03.239

F.27 Nramp1 Enhances Autoimmune DiabetogenicT Cell Response by Altering the Processing andPresentation of Pancreatic Islet Antigens inDendritic CellsYang Dai, Research Scientist, Torrey Pines Institute forMolecular Studies, San Diego, CA, Babak Shirdel, Student,Torrey Pines Institute for Molecular Studies, San Diego, CA,Sandra Chau, Student, Torrey Pines Institute for MolecularStudies, San Diego, CA, Linda Wicker, Professor, CambridgeInstitute for Medical Research, Cambridge, Philippe Gros,Professor, McGill University, Montreal, QC, Canada, EliSercarz, Professor, Torrey Pines Institute for MolecularStudies, San Diego, CA

Dendritic cells are essential for initiating adaptive immuneresponses and establishing self tolerance. We hypothesizethat the antigen processing machinery differs betweendiabetes-susceptible and -resistant, MHC-matched indivi-duals, and that this difference contributes to the generationof pathogenic effectors rather than regulatory T cells indiabetes prone individuals. The Idd5.2 (insulin-dependentdiabetes 5.2) region contributes to the genetic susceptibilityof NOD (non-obese diabetes) mice to autoimmune diabetesand contains the gene encoding Nramp1 (natural resistance-associated macrophage protein 1). We found that Nramp1expression is not restricted to macrophages; importantly,

S25Abstracts