Research ArticleTransplantation

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

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Science Translational Medicine  11 Nov 2020:
Vol. 12, Issue 569, eaaw4744
DOI: 10.1126/scitranslmed.aaw4744

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Bring your own cytokine

T regulatory cells are a key part of the immune system, where they help suppress undesirable immune responses. Their potential therapeutic uses include various conditions caused by excessive or undesirable T cell activation, such as autoimmune disorders, graft-versus-host disease, and transplant rejection. To help maintain the activity of therapeutic T regulatory cells without concurrent activation of cytotoxic immune responses, Eskandari et al. equipped T regulatory cells with nanogel “backpacks” containing interleukin-2, engineered to release the cytokine under the appropriate conditions. The authors tested this approach in both murine and humanized models of skin transplantation, demonstrating the backpacked cells’ effectiveness at suppressing alloimmunity.


Adoptive cell transfer of ex vivo expanded regulatory T cells (Tregs) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such Treg therapies to the clinic has been slow. Because Treg 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 Treg 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 Tregs 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. Tregs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified Tregs or Tregs stimulated with systemic IL-2. We demonstrate that murine and human NG–modified Tregs carrying an IL-2 cargo perform better than conventional Tregs in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve Treg transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed Tregs.

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