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Tolerance Induction in Diabetogenic BDC-2.5 T cells

ABSTRACT: CD4 T cells play a critical role in promoting the development of autoimmunity in Type 1 Diabetes (T1D). The diabetogenic CD4 T cell clone BDC-2.5, originally isolated from a non-obese diabetic (NOD) mouse, has been widely used to study the contribution of autoreactive CD4 T cells and relevant antigens to autoimmune diabetes. Recent work from our lab has shown that the antigen for BDC-2.5 T cells is a hybrid insulin peptide (2.5HIP) consisting of an insulin C-peptide fragment fused to a peptide from chromogranin A (ChgA), and that endogenous 2.5HIP-reactive T cells are major contributors to autoimmune pathology in NOD mice. The objective of this study was to determine if poly(lactide-co-glycolide) (PLG) nanoparticles (NPs) loaded with the 2.5HIP antigen (2.5HIP-PLG) can tolerize BDC-2.5 T cells. Infusion of 2.5HIP-PLG NPs was found to prevent diabetes in an adoptive transfer model by impairing the ability of BDC-2.5 T cells to produce pro-inflammatory cytokines through induction of anergy, leading to an increase in the ratio of Foxp3+ regulatory T cells to IFN-γ+ effector T cells. This work is the first to use a hybrid insulin peptide, or any neoepitope, to re-educate diabetogenic T cells and may have significant implications for the development of an antigen-specific therapy for T1D patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE126553 | GEO | 2019/04/23

REPOSITORIES: GEO

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Project description:We demonstrate diverse roles of interferonâgamma (IFN-Î³) in the induction and regulation of immune-mediated inflammation using a transfer model of autoimmune diabetes. The diabetogenic CD4+BDC2.5 (BDC) T cell clone upon transfer into NOD.scid mice induced destruction of islets of Langerhans leading to diabetes. Administration of a neutralizing antibody to IFN-Î³ (H22) resulted in long term protection (LTP) from diabetes, with inflammation but persistence of a significant, albeit decreased numbers of Î²-cells. BDC T cells were a mixture of cells expressing high, intermediate and low levels of the T cell receptor. Clonotype-low BDC T cells were required for LTP. Furthermore, islet infiltrating leukocytes in the LTP mice contained Foxp3+CD4 T cells. Islet inflammation in both diabetic and LTP mice was characterized by heavy infiltration of macrophages. Gene expression profiles indicated that macrophages in diabetic mice were M1-type, while LTP mice contained M2-differentiated. The LTP was abolished if mice were treated with either an antibody depleting CD4 T cells, or a neutralizing antibody to CTLA-4, in this case, only at a late stage. Neutralization of IL-10, TGF-Î², GITR or CD25 had no effect. Transfer of only clonotype-high expressing BDC T cells induced diabetes but in contrast, H22 antibodies did not inhibit diabetes. While clonotype high T cells induced diabetes even when IFN-Î³ was neutralized, paradoxically, there was reduced inflammation and no diabetes if host myeloid cells lacked IFN-Î³ receptor. Hence, using monoclonal CD4 T cells, IFN-Î³ can have a wide diversity of roles, depending on the setting of the immune process. Experiment Overall Design: Pancreatic islets were laser-capture microdissected from mice injected with diabetogenic T cells. One cohort of mice also received injections with anti-interfereon gamma monoclonal antibody, which protected those mice from developing diabetes. RNA prepared from islets was amplified and analyzed by Affymetrix GeneChips. Each GeneChip was prepared from RNA pooled from 5 mice at each timepoint. GeneChips were prepared from RNA extracted at different days following injection of T cells. The following days were assayed day 0 (i.e., untreated), day 3 (for diabetic and protected islets), day 4 (diabetic and protected), day 5 (only for protected, as diabetic islets were too edematous to dissect), day 8 (diabetic and protected).

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Tolerance Induction in Diabetogenic BDC-2.5 T cells

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