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Rohit D Divekar,
Cara L Haymaker,
Jason A Cascio,
Betul F Guloglu,
Jason S Ellis,
Danielle M Tartar,
Christine M Hoeman,
Craig L Franklin,
Bernd H Zinselmeyer,
Jennifer N Lynch,
Mark J Miller,
Habib Zaghouani
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ABSTRACT: The cell dynamics associated with induction of peripheral T cell tolerance remain largely undefined. In this study, an in vivo model was adapted to two-photon microscopy imaging, and T cell behavior was analyzed on tolerogen-induced modulation. FcγR-deficient (FcγR(-/-)) mice were unable to resist or alleviate experimental allergic encephalomyelitis when treated with Ig-myelin oligodendrocyte glycoprotein (MOG) tolerogen, an Ig carrying the MOG35-55 peptide. However, when FcγR(+/+) dendritic cells (DCs) are adoptively transferred into FcγR(-/-) mice, uptake and presentation of Ig-MOG occurs and the animals were able to overcome experimental allergic encephalomyelitis. We then fluorescently labeled FcγR(+/+) DCs and 2D2 MOG-specific TCR-transgenic T cells, transferred them into FcγR(-/-) mice, administered Ig-MOG, and analyzed both T cell-DC contact events and T cell motility. The results indicate that tolerance takes place in lymphoid organs, and surprisingly, the T cells do not become anergic but instead have a Th2 phenotype. The tolerant Th2 cells displayed reduced motility after tolerogen exposure similar to Th1 cells after immunization. However, the Th2 cells had higher migration speeds and took longer to exhibit changes in motility. Therefore, both Th1 immunity and Th2 tolerance alter T cell migration on Ag recognition, but the kinetics of this effect differ among the subsets.
The Journal of Immunology 09/2011; 187(8):3979-86. · 5.79 Impact Factor
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Ping Yu,
Cara L Haymaker, Rohit D Divekar,
Jason S Ellis,
John Hardaway,
Renu Jain,
Danielle M Tartar,
Christine M Hoeman,
Jason A Cascio,
Austin Ostermeier,
Habib Zaghouani
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ABSTRACT: Lately, it has become clear that regulatory T cells (Tregs) play a major role in the maintenance of peripheral tolerance and control of autoimmunity. Despite these critical functions, the process underlying the development of Tregs remains largely undefined. Herein, altered peptide ligand (APL) variants derived from the proteolipid protein-1 (PLP1) epitope were expressed on immunoglobulins (Igs) and the resulting Ig-APLs were used to deliver the APLs from mother to fetus through the maternal placenta to influence thymic T cell selection. This delivery system was then adapted to the SJL/J mouse, a strain that expresses only the DM20 form of PLP, which lacks the dominant PLP1 epitope in the thymus during fetal and neonatal development. This model, which restores thymic T cell selection for PLP1, was then used to determine whether affinity plays a role in the development of Tregs. The findings show that fetal exposure to low-affinity peptide ligand was unable to drive development of Tregs while variants with higher affinity to the TCR resulted in significant seeding of the periphery with mature, naive Tregs. Thus, contrary to pathogenic T cells, Tregs require avid TCR-ligand interaction to undergo thymic development and maturation.
The Journal of Immunology 08/2008; 181(1):73-80. · 5.79 Impact Factor
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ABSTRACT: A number of Ag-specific approaches have been developed that ameliorate experimental allergic encephalomyelitis (EAE), an animal model for the human autoimmune disease multiple sclerosis. Translation to humans, however, remains a consideration, justifying the search for more insight into the mechanism underlying restoration of self-tolerance. Ig-proteolipid protein (PLP) 1 and Ig-myelin oligodendrocyte glycoprotein (MOG) are Ig chimeras carrying the encephalitogenic PLP 139-151 and MOG 35-55 amino acid sequence, respectively. Ig-PLP1 ameliorates EAE in SJL/J (H-2(s)) mice while Ig-MOG modulates the disease in C57BL/6 (H-2(b)) animals. In this study, we asked whether the chimeras would suppress EAE in F(1) mice expressing both parental MHC alleles and representing a polymorphism with more relevance to human circumstances. The results show that Ig-MOG modulates both PLP1 and MOG peptide-induced EAE in the F(1) mice, whereas Ig-PLP1 counters PLP1 EAE but exacerbates MOG-induced disease. This in trans aggravation of MOG EAE by Ig-PLP1 operates through induction of PLP1-specific T cells producing IL-5 that sustained inhibition of MOG-specific Abs leading to exacerbation of EAE. Thus, in trans T cell tolerance, which should be operative in polymorphic systems, can aggravate rather than ameliorate autoimmunity. This phenomenon possibly takes place through interference with protective humoral immunity.
The Journal of Immunology 03/2008; 180(3):1508-16. · 5.79 Impact Factor
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ABSTRACT: Currently, transition of T cells from effector to memory is believed to occur as a consequence of exposure to residual suboptimal Ag found in lymphoid tissues at the waning end of the effector phase and microbial clearance. This led to the interpretation that memory arises from slightly activated late effectors producing reduced amounts of IFN-gamma. In this study, we show that CD4 T cells from the early stage of the effector phase in which both the Ag and activation are optimal also transit to memory. Moreover, early effector T cells that have undergone four divisions expressed significant IL-7R, produced IFN-gamma, and yielded rapid and robust memory responses. Cells that divided three times that had marginal IL-7R expression and no IFN-gamma raised base level homeostatic memory, whereas those that have undergone only two divisions and produced IFN-gamma yielded conditioned memory despite low IL-7R expression. Thus, highly activated early effectors generated under short exposure to optimal Ag in vivo develop into memory, and such transition is dependent on a significant production of the cell's signature cytokine, IFN-gamma.
The Journal of Immunology 02/2008; 180(1):179-87. · 5.79 Impact Factor
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Renu Jain,
Danielle M Tartar,
Randal K Gregg, Rohit D Divekar,
J Jeremiah Bell,
Hyun-Hee Lee,
Ping Yu,
Jason S Ellis,
Christine M Hoeman,
Craig L Franklin,
Habib Zaghouani
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ABSTRACT: The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206-220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon gamma (IFNgamma) protect against passive TID. Because IFNgamma is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and beta-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNgamma that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNgamma led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNgamma induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17-producing cells.
Journal of Experimental Medicine 02/2008; 205(1):207-18. · 13.85 Impact Factor
