Immunoregulatory T cells, and particularly CD4+ regulatory T cells (Tregs), are central agents of immune tolerance. Tellingly, dysfunction or deficiency of Tregs is a key driver of both autoimmunity and allograft rejection. While a growing number of clinical trials proves the feasibility and safety of using expanded, natural, polyclonal immunoregulatory T cell therapeutics, their clinical efficacy remains ill-defined and limited. To bridge the gap, not only more studies toward adoptive Treg therapies (ATTs) are needed, but also engineered, precision ATTs acting as “living” drugs to overcome the low potency, poor persistence, and inability to traffic to and accumulate at inflammatory tissue sites that riddles unmodified ATTs. This Research Topic seeks submissions from scientists working on engineered T cell therapeutics in autoimmunity and transplantation that promise specific, potent, and durable immune suppression.

The goal of this Research Topic is to explore next-generation engineered T cell therapeutics geared towards autoimmune diseases and transplantation. Key advances may include conferral of high-avidity antigen-specificity to T cell therapeutics using Chimeric Antigen Receptors (CARs) or engineered T-cell Receptors (TCRs). Secondary challenges of ATTs that this Research Topic aims to address include: (1) Improving the understanding and controlled manipulation of Treg phenotypic stability (and prevention of the conversion to pro-inflammatory effectors in inflammatory microenvironments); (2) Engineering of enhanced trafficking by ATTs to target organs beyond antigen-dependent retention; (3) Promoting the in vivo persistence and function of ATTs through novel, selective cytokine signaling pathways; (4) Design and validation of safety switches in immunoregulatory ATTs that ensure clinical control.
By focusing on these topics, this collection will highlight innovative molecular, genetic, and epigenetic strategies under development to create safe, "armored," and effective ATTs.

We welcome contributions that advance our understanding of engineered T cell therapeutics from bench-to-bedside, through Original Research, Reviews, Mini Reviews, and Brief Research Reports on the following themes:

• Novel CAR-Treg and TCR-Treg constructs for autoimmunity or transplantation.

• Strategies to enhance Treg stability (e.g., CRISPR-based gene editing, epigenetic modulation of the FOXP3 locus, disruption of instability pathways).

• Engineering improved homing (e.g., transgenic chemokine receptors) and persistence (e.g., orthogonal cytokine systems).

• Advances in pre-clinical validation (e.g., humanized mouse models) and clinically-translatable in vivo cell tracking

• Process development for clinical-scale cGMP manufacturing, cell sourcing (including iPSC-derived), and product characterization.

Topic Editor Roberto Castro-Gutierrez declares being in the process of filing a patent on Treg engineering strategies for Type 1 Diabetes. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

Are you interested in contributing a manuscript to this Research Topic?

Engineered T Cell Therapeutics in Autoimmunity and Transplantation