title: Age-dependent divergent effects of OX40L treatment on the development of diabetes in NOD mice.
abstract: Earlier, we have shown that GM-CSF derived bone marrow (BM) dendritic cells (G-BMDCs) can expand Foxp3(+) regulatory T-cells (Tregs) through a TCR-independent, but IL-2 dependent mechanism that required OX40L/OX40 interaction. While some reports have shown suppression of autoimmunity upon treatment with an OX40 agonist, others have shown exacerbation of autoimmune disease instead. To better understand the basis for these differing outcomes, we compared the effects of OX40L treatment in 6-week-old pre-diabetic and 12-week-old near diabetic NOD mice. Upon treatment with OX40L, 6-week-old NOD mice remained normoglycemic and showed a significant increase in Tregs in their spleen and lymph nodes, while 12-week-old NOD mice very rapidly developed hyperglycemia and failed to show Treg increase in spleen or LN. Interestingly, OX40L treatment increased Tregs in the thymus of both age groups. However, it induced Foxp3(+)CD103(+)CD38(-) stable-phenotype Tregs in the thymus and reduced the frequency of autoreactive Teff cells in 6-week-old mice; while it induced Foxp3(+)CD103(-)CD38(+) labile-phenotype Tregs in the thymus and increased autoreactive CD4(+) T cells in the periphery of 12-week-old mice. This increase in autoreactive CD4(+) T cells was likely due to either a poor suppressive function or conversion of labile Tregs into Teff cells. Using ex vivo cultures, we found that the reduction in Treg numbers in 12-week-old mice was likely due to IL-2 deficit, and their numbers could be increased upon addition of exogenous IL-2. The observed divergent effects of OX40L treatment were likely due to differences in the ability of 6- and 12-week-old NOD mice to produce IL-2.
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Haddad
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Palash
authors.initials: P
authors.lastname: Bhattacharya
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Khaled
authors.initials: K
authors.lastname: Alharshawi
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Marinelarena
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Prabhakaran
authors.initials: P
authors.lastname: Kumar
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Osama
authors.initials: O
authors.lastname: El-Sayed
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Elshabrawy
authors.affiliation: b Department of Pathology , University of Southern California Keck School of Medicine , Los Angeles , CA , USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
authors.affiliation: a Department of Microbiology and Immunology , University of Illinois College of Medicine , Chicago , IL , USA and.
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D019264:Adoptive Transfer; D000367:Age Factors; D000818:Animals; D001786:Blood Glucose; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000008:administration & dosage / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology* / Q000378:metabolism*; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D011485:Protein Binding; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Foxp3; IL-2; Regulatory T-cells; labile Tregs; stable Tregs