In Vivo Enrichment of Diabetogenic T Cells

Abstract

Dysfunctional T cells can mediate autoimmunity, but the inaccessibility of autoimmune tissues and the rarity of autoimmune T cells in the blood hinder their study. We describe a method to enrich and harvest autoimmune T cells in vivo by using a biomaterial scaffold loaded with protein antigens. In model antigen systems, we found that antigen-specific T cells become enriched within scaffolds containing their cognate antigens. When scaffolds containing lysates from an insulin-producing β-cell line were implanted subcutaneously in autoimmune diabetes–prone NOD mice, β-cell–reactive T cells homed to these scaffolds and became enriched. These T cells induced diabetes after adoptive transfer, indicating their pathogenicity. Furthermore, T-cell receptor (TCR) sequencing identified many expanded TCRs within the β-cell scaffolds that were also expanded within the pancreata of NOD mice. These data demonstrate the utility of biomaterial scaffolds loaded with disease-specific antigens to identify and study rare, therapeutically important T cells.

Immunomodulatory Dual-Sized Microparticle System Conditions Human Antigen Presenting Cells Into a Tolerogenic Phenotype In Vitro and Inhibits Type 1 Diabetes-Specific Autoreactive T Cell Responses

“…Notably, while the specific dMP formulation is tunable for disease-specific applications, the combination of agents in the dMP tested here synergized to influence T cell effector function. This may provide additional benefit in the case of antigenspecific T cell localization to a peripheral antigen depot, as recently reported in an antigen-defined T1D mouse model (87).…”

Treating ischemia via recruitment of antigen-specific T cells

“…These findings are consistent with previous work. The same PLG-scaffold system used in this study was previously shown to enrich antigen-specific CD4 + and CD8 + T cells inside the scaffold when providing controlled delivery of either OVA or β cell lysate subcutaneously ( 24 ). Similarly, persistent presentation of gp100 melanoma peptide in incomplete Freund’s adjuvant, which protects the antigen from degradation, led to sequestration of antigen-specific CD8 + T cells at the vaccine site ( 26 ).…”

“…To test this hypothesis, mice were first vaccinated using the model antigen ovalbumin (OVA) in the presence of aluminum (as a mimic for childhood vaccines) and later received an implantation of OVA-containing scaffolds in their ischemic hindlimbs. This vascularization strategy relies on (i) the widely accepted ability of aluminum as an adjuvant to generate memory T H 2 T cells when used in combination with an antigen ( 23 ) and (ii) our previous work demonstrating that antigen-containing polymer scaffolds can enrich for antigen-specific T cells to the scaffold site ( 24 ).…”

Engineering Immune Tolerance with Biomaterials

“…Scaffolds provide a high level of control over the spaciotemporal presentation of self‐antigens and regulatory cues, and this ability can aid in directing the phenotype of infiltrating cells. Further, scaffolds can be retrieved after implantation or injection, serving as a unique mechanistic tool to monitor local immune response . The potential of harnessing scaffolds to engineer antigen‐specific immune response have been previously demonstrated by the Mooney group.…”