PERSPECTIVE article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
This article is part of the Research TopicA Nanoparticle-Antibody Alliance: A New Era in Disease DiagnosticsView all articles
CD2 Targeted Nanoparticles Containing IL-2 Mimic Fetal-Maternal Tolerance of Pregnancy by Inducing Synergistic TGF-β-producing NK cells and Tregs
Provisionally accepted
- 1Keck School of Medicine, University of Southern California, Los Angeles, United States
- 2General Nanotherapeutics, LLC, Santa Monica,, United States
- 3University of California Los Angeles Department of Medicine, Los Angeles, United States
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Abstract T regulatory cells (Tregs) are essential for maintaining immune homeostasis and tolerance. We have reported that CD2-targeted nanoparticles containing IL-2 induce CD4 and CD8 Foxp3+ Tregs, together with TGF-β-producing CD56bright NK cells. Generation and maintenance of stable Tregs critically depended on TGF-β dependent interactions between these adaptive and innate immune cells. This resembles what occurs in maternal-fetal tolerance in pregnancy, where TGF-β from uterine stromal cells and fetal trophoblasts induces NK cells and T cells to become decidual Tregs and NK cells that prevent fetal rejection. Thus, both in the periphery and in utero, a TGF-dependent crosstalk between NK cells and Tregs appears vital for maintaining immune tolerances. This mimicry of maternal-fetal tolerance has clinical relevance. Subjects with SLE and other autoimmune disorders have deficits in IL-2, TGF-β and NK cells. It is likely that recent clinical trials in these diseases with IL-2 that did not reach their primary end points had failed to fully address these defects. Our anti-CD2 conjugated NPs target CD2-bearing T cells and NK cells and provide them in vivo both IL-2 and TGF-β. The NPs do not necessitate TGF-β because the NK cell-derived TGF-β produced locally by the target cells is sufficient to sustain Tregs. For these reasons, we believe our NP platform may have great potential not only for the prevention and/or treatment of a wide variety of immune-mediated disorders, but also to prevent recurrent miscarriages.
Keywords: Maternal-fetal tolerance, T regulatory cells (Tregs), natural killer (NK) cells, Transforming growth factor β (TGF-β), Nanoparticles
Received: 25 Aug 2025; Accepted: 24 Oct 2025.
Copyright: © 2025 Horwitz and La Cava. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: David A Horwitz, dhorwitz@usc.edu
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