NFAT-dependent and -independent exhaustion circuits program maternal CD8 T cell hypofunction in pregnancy

Pregnancy is a common immunization event, but the molecular mechanisms and immunological consequences provoked by pregnancy remain largely unknown. We used mouse models and human transplant registry data to reveal that pregnancy induced exhausted CD8 T cells (Preg-TEX), which associated with prolonged allograft survival. Maternal CD8 T cells shared features of exhaustion with CD8 T cells from cancer and chronic infection, including transcriptional down-regulation of ribosomal proteins and up-regulation of TOX and inhibitory receptors. Similar to other models of T cell exhaustion, NFAT-dependent elements of the exhaustion program were induced by fetal antigen in pregnancy, whereas NFAT-independent elements did not require fetal antigen. Despite using conserved molecular circuitry, Preg-TEX cells differed from TEX cells in chronic viral infection with respect to magnitude and dependency of T cell hypofunction on NFAT-independent signals. Altogether, these data reveal the molecular mechanisms and clinical consequences of maternal CD8 T cell hypofunction and identify pregnancy as a previously unappreciated context in which T cell exhaustion may occur.

Paternal priming of maternal tissues to optimise pregnancy success

The question of ‘how does the allogeneic fetus survive gestation in the face of the maternal immune system?’ has yet to be definitively answered. Several acceptable mechanisms exist to facilitate survival of the semi-allogeneic fetus in various species; paramount is the immunological separation of maternal and fetal tissues during gestation. However, keen observation of the maternal immune system during pregnancy has noted maternal immune tolerance to paternal-specific antigens. A mechanism by which the maternal immune system tolerates specific paternal antigens expressed on the fetus would be far more beneficial than the previously proposed immune indolence that would leave the mother susceptible to infection. In species like human or rodent, implantation occurs days after fertilisation and, as such, the mechanisms to establish antigen-specific tolerance must be initiated very early during pregnancy. We and others propose that these mechanisms are initiated at the time of insemination when paternal antigens are first introduced to the maternal immune system. Indeed, a new paradigm demonstrating the importance of paternal–maternal communication at the time of insemination is becoming evident as it relates to maternal tolerance to fetal antigen and ultimately pregnancy success.

Corrigendum to: Paternal priming of maternal tissues to optimise pregnancy success

The question of ‘how does the allogeneic fetus survive gestation in the face of the maternal immune system?' has yet to be definitively answered. Several acceptable mechanisms exist to facilitate survival of the semi-allogeneic fetus in various species; paramount is the immunological separation of maternal and fetal tissues during gestation. However, keen observation of the maternal immune system during pregnancy has noted maternal immune tolerance to paternal-specific antigens. A mechanism by which the maternal immune system tolerates specific paternal antigens expressed on the fetus would be far more beneficial than the previously proposed immune indolence that would leave the mother susceptible to infection. In species like human or rodent, implantation occurs days after fertilisation and, as such, the mechanisms to establish antigen-specific tolerance must be initiated very early during pregnancy. We and others propose that these mechanisms are initiated at the time of insemination when paternal antigens are first introduced to the maternal immune system. Indeed, a new paradigm demonstrating the importance of paternal–maternal communication at the time of insemination is becoming evident as it relates to maternal tolerance to fetal antigen and ultimately pregnancy success.

Amniotic fluid embolism: the known and not known

Amniotic fluid embolism was first recognized in 1926, in a Brazilian journal case report, on the basis of large amounts of fetal material in the maternal pulmonary vasculature at autopsy. The first English language description appeared in 1941 and consisted of eight parturients dying suddenly in which, once again, fetal material was seen in the pulmonary vasculature. A control group of 34 pregnant women dying of other recognized causes did not have fetal material in their lungs. The incidence of recognized, serious illness is on the order of two to eight per 100,000, with a mortality rate ranging from 13% to 35%. The diagnosis rests largely on one or more of four clinical signs: circulatory collapse, respiratory distress, coagulopathy, and seizures/ coma. The only confirmatory laboratory test remains autopsy findings although serum tests for fetal antigen, insulin-like growth factor binding protein-1, and complement are currently being investigated. One of the paradoxes of diagnosis is that fetal material in the pulmonary circulation at autopsy is specific for amniotic fluid embolism, while the same finding in the living is not. The mechanism of disease remains uncertain although the best available evidence suggests that complement activation might have a role. In contrast, mast cell degranulation probably is not a mechanism, so amniotic fluid embolism is not an anaphylaxis or anaphylactoid reaction as has been occasionally suggested. Perhaps the greatest unknown is not why 1 in 50,000 pregnant women develop what appears to be an immune response to their fetus, but rather why the other 49,999 do not?