An Artificial Antigen-presenting Cell with Paracrine Delivery of IL-2 Impacts the Magnitude and Direction of the T Cell Response

Erin R. Steenblock,Tarek Fadel,Jordan S. Pober,Tarek M. Fahmy,Michael Labowsky

doi:10.1074/jbc.m111.276329

Erin R. Steenblock, Tarek Fadel + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m111.276329

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Abstract

Artificial antigen-presenting cells (aAPCs) are an emerging technology to induce therapeutic cellular immunity without the need for autologous antigen-presenting cells (APCs). To fully replace natural APCs, an optimized aAPC must present antigen (signal 1), provide costimulation (signal 2), and release cytokine (signal 3). Here we demonstrate that the spatial and temporal characteristics of paracrine release of IL-2 from biodegradable polymer aAPCs (now termed paAPCs) can significantly alter the balance in the activation and proliferation of CD8+ and CD4+ T cells. Paracrine delivery of IL-2 upon T cell contact with paAPCs induces significant IL-2 accumulation in the synaptic contact region. This accumulation increases CD25 (the inducible IL-2 Rα chain) on responding T cells and increases proliferation of CD8+ T cells in vitro to levels 10 times that observed with equivalent amounts of bulk IL-2. These CD8+ T cell responses critically depend upon close contact of T cells and the paAPCs and require sustained release of low levels of IL-2. The same conditions promote activation-induced cell death in CD4+ T cells. These findings provide insight into the response of T cell subsets to paracrine IL-2.

Highlights

By facilitating IL-2 delivery from CD4ϩ T cells to CD8ϩ T cells
We show that CD8ϩ T cells proliferate vigorously in response to paracrine IL-2 delivery by polymeric artificial antigen-presenting cell (paAPC), whereas CD4ϩ T cell expansion is limited by apoptosis
The closest encounter (Fig. 1A, right panel) IL-2 is delivered by paAPCs that that are separated from T cells only by the nanoscale molecular interactions involving anti-CD3 and anti-CD28 binding to their ligands on T cells

Summary

Introduction

By facilitating IL-2 delivery from CD4ϩ T cells to CD8ϩ T cells. This is accomplished by bringing CD4ϩ and CD8ϩ lymphocytes into close contact [1, 7]. PaAPCs releasing IL-2 produced higher levels of CD25 on the surface of CD4ϩ and CD8ϩ T cells (Fig. 1C) and greater T cell activation as measured by secretion of IL-2 and IFN-␥ and resulted in increased expansion of CD8ϩ T cells (Fig. 1B and supplemental Fig. S1).

Results

Conclusion