Antigen-conjugated scaffolds enable sustained delivery of antigen and enrichment of antigen-specific T-cells.

A thorough understanding of T-cell dynamics and interactions could improve patient care in autoimmunity, cancer immunotherapy, and myriad other conditions, yet monitoring antigen-specific T-cell clones is challenging. T-cells recognize antigens presented by antigen-presenting cells (APCs) in the context of major histocompatibility complexes (MHCs). Specific T-cell clones are rare in the blood (<1 in 100,000), and thus cell expansion which consequently alters cell phenotype and function is typically necessary before analysis. This motivates the development of new methods for enriching T-cell populations of interest without phenotypically altering them. Recent work has demonstrated that implantable biomaterial systems can recruit disease-relevant cells in autoimmune conditions, and that if antigens are present, antigen-specific T-cells become enriched in these materials. To date, antigen-loaded materials have exhibited uncontrolled loading, burst release, and subsequent T-cell exhaustion. In this report, we engineer a novel biomaterial antigen delivery system by conjugating antigens to the polymer backbone prior to porous scaffold fabrication. We demonstrate that this technique enables precise antigen loading via ratiometric mixing of modified and unmodified polymer. We show controlled release of antigen into the microenvironment and demonstrate that released antigen is processed and presented by APCs. Using this fabrication method, we achieve sustained release of peptide antigens over a period of 3 weeks in vitro. When implanted in healthy mice, these antigen-conjugated scaffolds are invaded by host myeloid and lymphoid cells and exhibit a dose-dependent enrichment of systemically circulating antigen-specific T-cell populations, while avoiding significant T-cell exhaustion. Finally, we apply this system to an autoantigen from multiple sclerosis (MS) and show release and interaction with autoantigen-specific T-cells. Using this technique, disease-relevant T-cells can be recruited for diagnostic assessment or for immunological research. Future work will investigate the potential of these systems to monitor disease onset and progression in vivo, co-deliver multiple antigens for assessment of epitope spreading, therapeutically target disease-relevant cells within a local niche in situ, and expand the platform for controlled delivery of therapeutic peptides in models beyond autoimmunity.