(209i) Biomaterial Scaffold for the Generation of Regulatory T Cells

Regulatory T cells (T_regs) are a subpopulation of immune cells dedicated to maintaining self-tolerance and homeostasis, and suppressing excessive inflammation. They are used preclinically as an immunotherapy to treat autoimmune and graft-versus-host diseases, and to improve solid organ acceptance [1]. Conventionally, autologous T_regs are isolated from patients, expanded ex vivo, and reinfused. Some of the main challenges to the clinical translation of T_reg therapies are long manufacturing times, high costs, and low in vivo viability and persistence [2]. We addressed these limitations by developing a biomaterial-based tolerogenic niche that recruits endogenous conventional T cells and converts them into a regulatory phenotype directly in vivo.

We formed collagen-norbornene–alginate-tetrazine cryogels that are injectable on a minimally-invasive manner [3]. We loaded the chemokine C-X-C motif chemokine ligand 10 (CXCL10) to locally recruit T cells to the scaffold and included an immunosuppressive small molecule to convert recruited conventional T cells into T_regs. Importantly, since T cells need interleukin-2 (IL-2) for their survival, and T_regs are unable to secrete autocrine IL-2, we compared tolerogenic niches with and without IL-2 [4].

In vitro, the cryogel provided a sustained release of all compounds over 2 to 5 days. Our tolerogenic niche was injected subcutaneously in C57BL/6 mice and, after 2 days, a local increase of T_regs (CD4+CD25+FOXP3+) was found when compared to blank scaffolds. We found that the addition of IL-2 was necessary to boost T_reg levels in the tolerogenic niche to significant levels. We are currently evaluating the therapeutic potential of the developed scaffolds in disease models marked by excessive inflammation.

In total, we demonstrate that tolerogenic biomaterial niches locally recruit and promote T_reg formation. We expect that these systems will simplify and expedite the clinical translation of T_reg-based immunotherapies.

References:
[1] L.M.R. Ferreira and Y.D. Muller et al., Nat. Rev. Drug Discovery, 2019, 18:749
[2] L. Amini et al., Front. Cell Dev. Biol., 2022, 10:1081644
[3] K. Adu-Berchie et al., Nat. Commun., 2023, 14:3546
[4] B.H. Nelson, J. Immunol, 2004, 7:3983