UCSF

The developing immune system has long been recognized to be uniquely prone to tolerance induction. Historical observations in rodent models, suggest that the tolerogenic properties of the fetus and neonate are linked to the immaturity of the adaptive immune system at this stage of development. However, the adaptive immune system of larger mammals undergoes considerable maturation during fetal development and is not thought to be amenable to tolerance induction at this time. There have, however, been clinical observations that suggest that the human fetus may be subject to tolerance induction under certain conditions, though very little is known about the mechanisms underlying such tolerance. This is in part attributable to a general deficit of knowledge concerning the functional properties of the developing immune system in human beings.

We characterized fetal T cells at early stages of T cell development (10-20 gestational weeks (g.w.)). Our analysis revealed that a high frequency of fetal CD4+ T cells bore the phenotype of regulatory T cells (TReg). Analysis of neonatal cord blood and adult peripheral blood and lymphoid tissues revealed that fetal tissues contained greater frequencies of TReg than neonates or adults.

These observations, coupled with the clinical findings that certain individuals showed tolerance to non-inherited maternal HLA molecules in a transplant setting, led to the hypothesis that fetal TReg could play a role in suppressing T cell responses to maternal alloantigens. A survey of lymph node specimens revealed that maternal cells could be detected within the developing fetal tissues. Fetal T cells were highly responsive to alloantigens yet fetal TReg were capable of suppressing fetal T cell responses to maternal alloantigens. Stimulation of naïve fetal T cells with alloantigens led to the differentiation and expansion of TReg cells, providing a mechanism for how tolerance could be achieved following fetal exposure to foreign antigens in humans.

Ongoing studies have revealed that the tolerogenic properties of the developing fetal immune system may be rooted in changes that occur within the hematopoietic stem cell (HSC) compartment. These findings provide novel insights into the development of immunological tolerance in human beings.