Regulatory T cells (Tregs) are an important part of the immune system of vertebrates. They suppress the immune responses of other cells and help discriminate between self and non-self. Tregs have long been thought to play a role in tolerance of the placental semi-allograft, where half the proteins are coded by maternal genes and recognizable as “self,” but the others are coded by paternal genes and may be seen as “non-self.”
Two recent reports show that Tregs evolved along with the evolution of placentation in mammals. Both concern Foxp3, a transcription factor associated with Tregs. The first study explored the evolution of Foxp3 by comparative genomics. It was found to have undergone modifications that included addition of a proline-rich region that was already present in the platypus (a monotreme) and opossum (a marsupial) but further extended in placental mammals. The authors hypothesized that the proline-rich region allowed Foxp3 to bind factors involved in T cell activation and suggested this was part of a mechanism to suppress undesirable immune responses to the placenta.
The other paper went a step further and looked at CNS1, which is an enhancer of Foxp3 and important in the differentiation of Tregs at sites other than the thymus – including the endometrium. The enhancer was found in all placental mammals examined, but absent in the platypus, wallaby and opossum. The importance of the CNS1 gene in placental mammals was demonstrated by a higher rate of fetal loss in CNS1 knockout mice.
Other players are involved in immune tolerance of the placenta, but a central role for Tregs is implied by knowledge that evolution of Foxp3, as well as its enhancer CNS1, has occurred in tandem with the evolution of placentation.