Regulatory T cell homeostasis: Requisite signals and implications for clinical development of biologics

• Published in: Clinical immunology (Orlando, Fla.) Vol. 246; p. 109201
• Main Authors: Skartsis, Nikolaos, Muller, Yannick D., Ferreira, Leonardo M.R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023
• Subjects: Autoimmune Diseases - drug therapy; Autoimmunity; Biological Products - pharmacology; Biological Products - therapeutic use; Biologics; Homeostasis; Humans; Immune Tolerance; Inflammatory bowel disease; Pleiotropism; Regulatory T cells; Rheumatoid arthritis; Systemic lupus erythematous; T-Lymphocytes, Regulatory; Transplant rejection; Autoimmunity; Inflammatory bowel disease; Systemic lupus erythematous; Biologics; Rheumatoid arthritis; Transplant rejection; Regulatory T cells; Pleiotropism
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2022.109201

Novel biologics are currently being tested in clinical trials for the treatment of autoimmune diseases and the prevention of transplant allograft rejection. Their premise is to deliver highly efficient immunosuppression while minimizing side-effects, as they specifically target inflammatory mediators involved in the dysregulation of the immune system. However, the pleiotropism of soluble mediators and cell-to-cell interactions with potential to exert both proinflammatory and regulatory influences on the outcome of the immune response can lead to unpredictable results. Predicting responses to biologic drugs requires mechanistic understanding of the cell type-specific effect of immune mediators. Elucidation of the central role of regulatory T cells (Treg), a small subset of T cells dedicated to immune homeostasis, in preventing the development of auto- and allo-immunity has provided a deeper understanding of the signaling pathways that govern immune tolerance. This review focuses on the requisite signals that promote Treg homeostasis and discusses the anticipated outcomes of biologics targeting these signals. Our goal is to inform and facilitate the design of cell-specific biologics that thwart T effector cells (Teff) while promoting Treg function for the treatment of autoimmune diseases and the prevention of transplant rejection. •Treg homeostasis is dependent on requisite signals that may be shared with Teffs.•Biologic agents may cripple Treg homeostasis leading to detrimental outcomes.•Novel biologics that spare Tregs, but target Teffs are needed.