Regulatory T cells in transplantation: does extracellular adenosine triphosphate metabolism through CD39 play a crucial role?
Despite tremendous improvements in short-term renal allograft survival, many patients still have chronic rejection or side effects of nonspecific immunosuppression. The discovery of Foxp3(+) regulatory T cells (Tregs) has revolutionized the concepts in immunoregulation and offers perspectives for overcoming rejection. Recently, a subset of Foxp3(+)CD39(+) effector/memory-like Tregs (T(REM)) was identified. The role of CD39(+) Tregs in immunoregulation is supported by the occurrence of alopecia areata and experimental autoimmune encephalomyelitis in CD39-deficient mice and by the failure of CD39(-) Tregs to suppress contact hypersensitivity. In humans, CD39 polymorphisms have been associated with diabetes and nephropathy, and multiple sclerosis patients have reduced numbers of blood CD39(+) Tregs. Preliminary experiments in a murine transplantation model showed that CD39(+) Tregs can determine allograft outcome. CD39 degrades the extracellular adenosine triphosphate (ATP) released during tissue injury, which otherwise would trigger inflammation. Currently, our groups are assessing the role of CD39(+) Tregs and extracellular ATP metabolism in clinical transplantation and whether tolerogenic Treg profiles possess immunopredictive value, envisioning the development of clinical trials using CD39(+) Treg-based vaccination for autoimmunity or transplantation. This is a comprehensive review on the fundamentals of Treg biology, the potential role of ATP metabolism in immunoregulation, and the potential use of Treg-based immunotherapy in transplantation.
Renal Medicine Department, Singapore General Hospital, Singapore. francisco.salcido.ochoa@singhealth.com.sg
Francisco
F
Salcido-Ochoa
Julia
J
Tsang
Paul
P
Tam
Kirsten
K
Falk
Olaf
O
Rotzschke
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001081:Apyrase / Q000276:immunology*; D002454:Cell Differentiation; D002465:Cell Movement; D051858:Forkhead Transcription Factors / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014181:Transplantation Immunology
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen