Foxp3 as a marker of tolerance induction versus rejection

Foxp3 is the transcription factor that induces the regulatory T cell phenotype. This review will examine issues around Foxp3 induction and function as well as clinical data on tolerance and rejection.

Recent findings have included identification of the signals that drive naive T lymphocytes to express Foxp3 in the thymus and the signals peripherally that induce non-Foxp3 expressing T cells to express FOXP3. Further, the identification of the downstream targets of Foxp3 both by analysis of Foxp3 expressing cells and by analysis of gene promoters that bind Foxp3 has provided new insights into its function. Whereas Foxp3 T regulatory cells (Tregs) are associated with tolerance in a variety of animal transplant models, the human data show expansion of Foxp3 Tregs associated with rejection, though Tregs are also found in transplants in patients with mixed chimerism-induced tolerance. Further, there is a significant difference in the effect of the different immunosuppressive medications on Treg function and expansion that may be important in developing strategies to enhance Tregs in human trials.

Foxp3 CD4 T cells are frequently associated with rejection; however, this does not preclude their protective role and importance in tolerance induction.