Abstract
T cells reacting to self-components can promote tissue damage when escaping tolerogenic control mechanisms which may result in autoimmune disease. The current treatments for these disorders are not antigen (Ag) specific and can compromise host immunity through chronic suppression. We have previously demonstrated that co-administration of encapsulated or free Ag with tolerogenic nanoparticles (tNPs) comprised of biodegradable polymers that encapsulate rapamycin are capable of inhibiting Ag-specific transgenic T cell proliferation and inducing Ag-specific regulatory T cells (Tregs). Here, we further show that tNPs can trigger the expansion of endogenous Tregs specific to a target Ag. The proportion of Ag-specific Treg to total Ag-specific T cells remains constant even after subsequent Ag challenge in combination with a potent TLR7/8 agonist or complete Freund’s adjuvant. tNP-treated mice do not develop experimental autoimmune encephalomyelitis (EAE) after adoptive transfer of encephalitogenic T cells; furthermore, tNP treatment provided therapeutic protection in relapsing EAE that was transferred to naïve animals. These findings describe a potent therapy to expand Ag-specific Tregs in vivo and suppress T cell-mediated autoimmunity.
Highlights
Maintenance of peripheral immunological tolerance is a dynamic and continuous process
We evaluated the activation of OTII transgenic T cells that recognize the 323–339 peptide of chicken ovalbumin (OVA323) after adoptive transfer into mice that were previously treated with NPs containing the OVA323 peptide alone (NP[OVA323]) or tolerogenic nanoparticles (tNPs) containing both OVA323 and rapamycin
Rag2−/−-recipient mice were used to ensure that no endogenous lymphocytes would compete with the OTII T cells for binding to OVA323 peptide presented by Ag-presenting cells
Summary
Maintenance of peripheral immunological tolerance is a dynamic and continuous process. Most self-reactive T lymphocytes are deleted in the thymus or differentiate into natural T regulatory cells (Tregs), but some can enter the pool of naive circulating cells. Self-reactive naive T cells that escape the thymus and encounter their cognate antigen (Ag) in the periphery can differentiate into induced Tregs [1, 2]. Tregs maintain immune homeostasis in vivo, and their dysfunction, caused by the loss of expression of the master transcription factor Foxp, leads to the development of immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) in humans characterized by systemic T cell activation and multiorgan autoimmunity [3]. Genetic and environmental factors result in the dysregulated expansion of autoreactive lymphocytes that mediate damage to self-tissue [4, 5].
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