Hormonally controlled ILC antigen presentation potential is reduced during pregnancy

Abstract

Strategically located in mucosal barriers, innate lymphoid cells (ILCs) are relevant in local containment and tolerance of commensal microflora. ILCs have been recently described at the fetomaternal interface, where the development of a semi-allogeneic fetus can only succeed in a well-controlled immune environment. We postulate that ILCs adapt their antigen presentation capacity to protect pregnancy from excessive immune responses. Human ILCs were studied in deciduae of term pregnancies, peripheral blood and in in vitro generated ILCs. Fresh isolated lymphocytes or cells treated with pregnancy-related factors were investigated. The fetal antigen rejection-based CBA/J × DBA/2J mouse model (poor outcome pregnant mice; POPM) was used to characterize ILC antigen presentation potential in normal and immunologically disturbed pregnancies. ILC antigen presentation potential was characterized by flow cytometry and qPCR. We discovered that the distribution of ILC subsets changed during both human and murine pregnancy. Moreover, the pregnancy was accompanied by reduced MHCII expression in splenic ILCs during normal pregnancy (CBA/J × BALB/c; good outcome pregnant mice; GOPM) but increased in splenic and intestinal ILCs of CBA/J × DBA/2J mice. In vitro, splenic ILCs from pregnant mice increased MHCII expression after stimulation with IL-1β and IL-23. In contrast, uterine ILCs displayed lower MHCII expression, which remained unchanged after stimulation. Finally, pregnancy-related factors and hormones present in the uterine environment reduced antigen presentation potential of human ILCs in vitro. Together, these data indicate that, during pregnancy, peripheral and especially uterine ILCs adapt their antigen presenting potential to maintain a level of tolerance and support pregnancy.

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

“…Particularly, the antigen presentation capacity of ILCs has been found to be fundamental in immune homeostasis, as for instance in the gut [12,14]. During pregnancy, we have observed that the antigen presentation potential of ILCs is reduced [15]. This phenomenon may represent an adaptive mechanism involved in the tolerance against fetal antigens.…”

“…Mononuclear cells were isolated as previously described [15]. Brie y, blood samples were centrifuged, serum discarded and cells were isolated by density centrifugation with Lymphoprep™ (STEMCELL Technologies Inc., Vancouver, Canada), following manufacturer's instructions.…”

Cord-Blood-Derived Professional Antigen-Presenting Cells: Functions and Applications in Current and Prospective Cell Therapies

“…ILC3s are among the innate immune cells that can traverse the placental barrier and may be vital in the defense against Toxoplasma gondii , which can be recognized by TLR2:1 [ 148 , 150 ]. In the presence of pregnancy-related factors and hormones in vivo in mice and in vitro in humans, ILCs display a reduced antigen presentation potential, evidenced by the lower expression of MHC II following inflammation [ 151 ]. This indicates that, during pregnancy, ILC functionality, in terms of antigen presentation, is redirected towards tolerance to support pregnancy [ 151 ].…”

“…In the presence of pregnancy-related factors and hormones in vivo in mice and in vitro in humans, ILCs display a reduced antigen presentation potential, evidenced by the lower expression of MHC II following inflammation [ 151 ]. This indicates that, during pregnancy, ILC functionality, in terms of antigen presentation, is redirected towards tolerance to support pregnancy [ 151 ]. Currently, no data are available on the antigen presentation capabilities of UCB ILC populations and further studies by multiple laboratories are needed to identify the therapeutic potential of UCB-derived ILCs.…”

Low Abundance Fusobacterium Nucleatum Supports Early Pregnancy Development – An In Vitro Study

“…Local and systemic immune adaptations facilitate the implantation and later the accommodation of the growing fetus (14)(15)(16)(17). These adaptations include the promotion of uterine vascular remodeling and the induction of immune tolerance (18)(19)(20)(21)(22)(23)(24). Both maternal lymphocytes and fetal derived cells including trophoblast establish a complex interaction to balance the inflammatory environment providing protection against pathogens and the necessary cytokine milieu that allows local structural modifications during placentation (17,25,26).…”