Forkhead box P family members at the crossroad between tolerance and immunity: A balancing act

Maintaining an immune balance between a chronic inflammatory state and autoimmunity is regulated at multiple levels by complex cellular signaling mechanisms. Numerous immune stimu- latory and inhibitory signals converge on a large variety of transcriptional regulators. One key transcriptional regulator of immune homeostasis is FOXP3, which is a member of the Forkhead Box P subfamily of transcription factors and was shown to be essential for the development and maintenance of regulatory T cells. However, other FOXP members have received less attention in relation to a role in immune regulation. Still, recent developments point toward a general important regulatory role for FOXP proteins in the development and function of the adaptive immune system and establishment of a balanced immune response. Here, we discuss the current knowledge on the role of FOXP proteins in establishing immune homeostasis with an emphasis on T-cell biology. Furthermore, we review and speculate about different modes of regulating general FOXP activity and the function of this in health and disease.