This proposal will focus on the development of tolerogenic vaccines that elicit responses of FOXP3+ regulatory T cells (Tregs) in murine models of EAE. This program will develop novel tolerogenic vaccines based on the use of Interferon- beta (IFN-?) as a tolerogenic adjuvant. Preliminary data indicated that these tolerogenic vaccines elicited a major FOXP3+ regulatory T cell (Treg) population because a single tolerogenic vaccination directly elicited FOXP3+ Tregs in vivo. Treatment of mice with an anti-CD25 mAb that depleted Tregs reversed vaccine-induced tolerance. Also, IFN-?- induced Tregs mediated the adoptive transfer of resistance to EAE. Three repeated immunizations with the tolerogenic vaccine elicited a persistent memory/ effector Treg subset. Our hypothesis is that tolerogenic vaccination drives tolerance via the induction of FOXP3+ Tregs and culminates in the induction of CTLA-4+ effector Tregs and a mechanism of infec- tious tolerance.
Aim 1 will test whether tolerogenic vaccination elicits polyclonal tolerance to NAg peptides by a mecha- nism dependent upon NAg-specific FOXP3+ Tregs. The approach will test multiple myelin peptides for tolerogenic vac- cination of transgenic TCR model systems in combination with FOXP3-reporter, fate-mapping Treg models and Treg de- pletion strategies to assess tolerance induction, function, phenotype, and stability of vaccine-induced Treg populations.
Aim 2 will assess induction and effector mechanisms of IFN-? induced FOXP3+ Tregs.
Aim 2 a will test whether IFN-? based tolerogenic vaccines elicit `nave', `central' or `effector' FOXP3+ T cells when the Type I IFNAR is absent in mye- loid cells, dendritic cells, pan T cells, or FOXP3+ T cells.
Aim 2 b will test whether IFN-? and NAg elicit FOXP3+ T cells that express the hallmarks infectious tolerance.
The aim i s based on the observation that CD45.2 FOXP3+ 2D2-FIG Tregs effectively directed the nascent differentiation of a nave population of FOXP3(null) CD45.1 T cells into a major FOXP3+ population in mixed activation cultures. The proposed research will provide novel information on tolerogenic vaccination and infectious tolerance via suppressive epitope spread among the major, MS-associated myelin NAg epitopes.
The project will advance a new class of tolerogenic vaccines that exploits the immunosuppressive activity of Interferon- beta as a tolerogenic adjuvant. Preliminary data has shown that these vaccines elicit immunosuppressive regulatory T cell populations and mediate both tolerogenic and therapeutic activity in widely-studied murine models of EAE. The proposed research promises to provide unique insight into basic mechanisms of immune system regulation and new avenues for development of tolerogenic vaccination as a therapy for Multiple Sclerosis.
| Wilkinson, Daniel S; Ghosh, Debjani; Nickle, Rebecca A et al. (2017) Partial CD25 Antagonism Enables Dominance of Antigen-Inducible CD25high FOXP3+ Regulatory T Cells As a Basis for a Regulatory T Cell-Based Adoptive Immunotherapy. Front Immunol 8:1782 |
| Wang, Duncheng; Ghosh, Debjani; Islam, S M Touhidul et al. (2016) IFN-? Facilitates Neuroantigen-Dependent Induction of CD25+ FOXP3+ Regulatory T Cells That Suppress Experimental Autoimmune Encephalomyelitis. J Immunol 197:2992-3007 |
