Regulatory T cell dysfunction and its implication for cell therapy.

Regulatory T cells (Tregs) are a subtype of CD4 + T cells that can mediate immune tolerance by a multitude of immunomodulatory mechanisms. Treg-based adoptive immunotherapy is currently being tested in multiple phase I and II clinical trials in transplantation and autoimmune diseases. We have learned from the work done on conventional T cells that distinct mechanistic states can define their dysfunctions, such as exhaustion, senescence and anergy. All three can negatively impact the therapeutic effectiveness of T-cell based therapies. However, whether Tregs are susceptible to such dysfunctional states is not well studied, and results are sometimes found to be controversial. In addition, Treg instability and loss of FOXP3 expression is another Treg-specific dysfunction that can lead to a decrease in their suppressive potential. A better understanding of Treg biology and pathological states will be needed to compare and interpret the results of the different clinical and preclinical trials. We will review herein the action mechanisms of Tregs, describe different T cell dysfunction subtypes and how and if they apply to Tregs (exhaustion, senescence, anergy and instability), and finally how this knowledge should be taken into consideration when designing and interpreting Treg adoptive immunotherapy trials.