Introduction
Regulatory T cells (Tregs) are a specialized subset of immune cells that regulate immune responses and maintain homeostasis. Defects in their development or function can lead to uncontrolled immune activation, resulting in inflammatory diseases like graft-versus-host disease, transplant rejection, and autoimmunity. Since Tregs utilize multiple molecular mechanisms to suppress immune responses, they hold potential as adaptive therapeutic agents for inflammatory disorders. Early clinical trials have demonstrated their feasibility, safety, and possible efficacy. Advancements in chimeric antigen receptor (CAR) technology and genome editing, including CRISPR–Cas9, have enhanced primary T cell therapies for cancer. These technologies are now being adapted to improve Treg cell specificity and functionality. This review highlights key advancements and prospects in Treg-based therapies for autoimmunity and transplantation. https://www.nature.com/articles/s41573-019-0041-4 Tregs and Immune Tolerance
Tregs maintain immune tolerance through the following :
Suppression of effector T cells and antigen-presenting cells.
Production of anti-inflammatory cytokines (IL-10, TGF-β, IL-35).
Metabolic disruption of effector T cells via IL-2 consumption.
Therapeutic Applications of Tregs :
Clinical trials using transferred Tregs began in 2009. The medical community is now exploring their therapeutic potential while adhering to safety guidelines as an alternative to conventional anti-inflammatory drugs. Tregs can be obtained from peripheral blood, umbilical cord blood, or the thymus (in experimental models).
Isolation is performed using gradient centrifugation to obtain mononuclear cells, followed by purification and enrichment to select Tregs based on CD4, CD25, and CD127 markers. Despite their high concentration in cord blood and thymus, isolation is challenging, necessitating ex vivo expansion using anti-CD3/CD28-coated beads with IL-2. To optimize yield and function, protocols incorporating rapamycin, IL-2, TGF-β, and all-trans retinoic acid (ATRA) have been explored, enhancing chemokine receptor expression for improved Treg homing, particularly in the gut.
Treg-based therapies are being investigated for organ transplantation, autoimmune diseases, cardiovascular conditions, obesity, and systemic inflammatory disorders. Clinical Trials in Autoimmune Diseases
Crohn’s Disease: Well tolerated in 54 patients; some adverse effects, but all recovered without complications.
Type 1 Diabetes: No serious adverse effects; trials completed without insulin dependency.
Key Challenges :
Stability: Some induced Tregs (iTregs) lose FOXP3 expression, converting into inflammatory cells.
Limited Availability: Natural Tregs (nTregs) comprise only 5–10% of CD4⁺ T cells, making large-scale expansion difficult.
Non-Specific Suppression: Polyclonal Tregs broadly suppress immune responses.
Enhancing Treg Specificity with CAR Technology
CAR technology has revolutionized treatments for B-cell malignancies and is now being explored to direct Tregs toward specific antigenic targets. CAR constructs typically include an extracellular signaling domain (scFv), a hinge region, a transmembrane domain, and an intracellular signaling component (e.g., CD3ζ with a co-stimulatory molecule like CD28). Notably, CD28 is crucial for maintaining CAR-Treg suppressive function.
Manufacturing autologous CAR-Tregs involves lentiviral or gamma-retroviral transduction of activated autologous T cells with a CAR-encoding vector, followed by expansion and administration. This approach holds promise for precision Treg therapy in immune-related disorders
Regulatory T cells (Tregs) play a vital role in maintaining immune balance and preventing excessive immune activation that can lead to autoimmune diseases, transplant rejection, and chronic inflammation. Advances in Treg-based therapies, including ex vivo expansion, cytokine modulation, and chimeric antigen receptor (CAR) technology, are paving the way for more precise and effective treatments. Despite challenges such as stability issues, limited availability, and non-specific suppression, ongoing research continues to refine strategies for enhancing Treg functionality and specificity. As our understanding of immune regulation deepens, Treg-based immunotherapies hold great promise for revolutionizing the treatment of autoimmune disorders, improving transplant outcomes, and expanding into new therapeutic areas. With further clinical advancements, these smart immune modulators may soon become a cornerstone of precision medicine. References :
. BY TANISH VARTAK
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