Lymph Node-Targeted Synthetically Glycosylated Antigen Leads to Antigen-Specific Immunological Tolerance

Abstract

Inverse vaccines that tolerogenically target antigens to antigen-presenting cells (APCs) offer promise in prevention of immunity to allergens and protein drugs and treatment of autoimmunity. We have previously shown that targeting hepatic APCs through intravenous injection of synthetically glycosylated antigen leads to effective induction of antigen-specific immunological tolerance. Here, we demonstrate that targeting these glycoconjugates to lymph node (LN) APCs under homeostatic conditions leads to local and increased accumulation in the LNs compared to unmodified antigen and induces a tolerogenic state both locally and systemically. Subcutaneous administration directs the polymeric glycoconjugate to the draining LN, where the glycoconjugated antigen generates robust antigen-specific CD4+ and CD8+ T cell tolerance and hypo-responsiveness to antigenic challenge via a number of mechanisms, including clonal deletion, anergy of activated T cells, and expansion of regulatory T cells. Lag-3 up-regulation on CD4+ and CD8+ T cells represents an essential mechanism of suppression. Additionally, presentation of antigen released from the glycoconjugate to naïve T cells is mediated mainly by LN-resident CD8+ and CD11b+ dendritic cells. Thus, here we demonstrate that antigen targeting via synthetic glycosylation to impart affinity for APC scavenger receptors generates tolerance when LN dendritic cells are the cellular target.

Tolerance Induced by Antigen-Loaded PLG Nanoparticles Affects the Phenotype and Trafficking of Transgenic CD4+ and CD8+ T Cells

“…Here, we have noted that this LAG-3 induction extends to CD8 + T cells as well. Another recent study using glycosylated antigen found a similar increase in LAG-3 + CD8 + cells following tolerization [ 42 ]. While we could confirm that LAG-3 + cells responded reluctantly to GP33 antigen compared to their LAG3- counterparts, no difference was observable between the treated and control groups ( Figure 5 C), and, in fact, the difference in the LAG-3 + levels disappeared over the course of the incubation ( Figure 5 B).…”

Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy

“…The glycopolymer-conjugated antigens target key immunomodulatory sites in the body, such as the liver and lymph nodes, via i.v. or s.c. administration routes, respectively, and are preferentially internalized by carbohydrate-binding receptors on APCs 18,19 .…”

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

“…In recent work, peptide antigens were glycosylated to increase uptake by tolerizing hepatic APCs. [93][94][95] By modifying antigens with Nacetylgalactosamine or N-acetylglucosamine and delivering intravenously, the authors were able to preferentially target the tolerizing hepatic APCs in the liver, allowing for increased generation of T REG and suppression of autoimmune diabetes. Carbohydrate linkers are designed to be cleaved intracellularly, allowing for presentation of unmodified antigen by APCs after uptake (Figure 5A).…”

“…A,B) Reproduced under the terms of the Creative Commons Attribution 4.0 International License. [ 94 ] Copyright 2021, The Authors. Published by Frontiers Media S.A. C) Paralysis level (disease severity) of mice treated with mannosylated antigens and D) proliferation in response to antigen with and without IL‐2 to measure anergy.…”

“…In addition to glycosylation and amphiphilic modification, peptide circulation, and potency has been increased using PE- [94] Copyright 2021, The Authors. Published by Frontiers Media S.A. C) Paralysis level (disease severity) of mice treated with mannosylated antigens and D) proliferation in response to antigen with and without IL-2 to measure anergy.…”