Immune Netw.  2023 Oct;23(5):e37. 10.4110/in.2023.23.e37.

Combined Treatment With TGF-β1, Retinoic Acid, and Lactoferrin Robustly Generate Inducible Tregs (iTregs) Against High Affinity Ligand

• Jang YS
• Park SH
• Kang SG
• Lee JS
• Ko HJ
• Kim PH

• KMID: 2549203
• DOI: http://doi.org/10.4110/in.2023.23.e37

Abstract

Forkhead box P3-positive (Foxp3 + )-inducible Tregs (iTregs) are readily generated by TGF-β1 at low TCR signaling intensity. TGF-β1–mediated Foxp3 expression is further enhanced by retinoic acid (RA) and lactoferrin (LF). However, the intensity of TCR signaling required for induction of Foxp3 expression by TGF-β1 in combination with RA and LF is unknown. Here, we found that either RA or LF alone decreased TGF-β1–mediated Foxp3 expression at low TCR signaling intensity. In contrast, at high TCR signaling intensity, the addition of either RA or LF strongly increased TGF-β1–mediated Foxp3 expression. Moreover, decreased CD28 stimulation was more favorable for TGF-β1/LF–mediated Foxp3 expression. Lastly, we found that at high signaling intensities of both TCR and CD28, combined treatment with TGF-β1, RA, and LF induced robust expression of Foxp3, in parallel with powerful suppressive activity against responder T cell proliferation. Our findings that TGFβ/RA/LF strongly generate high affinity Ag-specific iTreg population would be useful for the control of unwanted hypersensitive immune reactions such as various autoimmune diseases.

Keyword

Lactoferrin; Transforming growth factor beta; Retinoic acid; Regulatory T cells; forkhead box P3 protein; T cell receptor; CD28 antigen