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Adoptive cell transfer of ex vivo expanded regulatory T cells (T regs ) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such T reg therapies to the clinic has been slow. Because T reg homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous interleukin-2 (IL-2), some investigators have explored the use of low-dose IL-2 injections to increase endogenous T reg responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Here, we describe a drug delivery platform, which can be engineered to autostimulate T regs with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis( N -hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR. T regs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified T regs or T regs stimulated with systemic IL-2. We demonstrate that murine and human NG-modified T regs carrying an IL-2 cargo perform better than conventional T regs in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve T reg transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed T regs .

Regulatory T cells engineered with TCR signaling–responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter