Postdoctoral Fellow University of Chicago Chicago, Illinois, United States
Disclosure(s):
Alexander Nelson, PhD: No financial relationships to disclose
Introduction/Rationale: Sensitization to non-self human leukocyte antigen (HLA) is a barrier to transplant tolerance and graft survival. During pregnancy in humans, exposure to paternal HLA expressed by the semi-allogeneic fetus can induce the production of anti-HLA antibodies and memory B cells despite spontaneous T cell tolerance. Although murine studies suggest that pregnancy elicits B cell responses distinct from those in transplant rejection, the mechanisms driving humoral sensitization to fetal antigens remain poorly defined.
Methods: To investigate the mechanisms that underlie humoral sensitization in pregnancy, we modeled semi-allogeneic pregnancy by mating C57BL/6 female mice to BALB/c males expressing the model antigen 2W1S-OVA (2W-B/c) to enable the identification of fetus-specific T cells. Fetus-specific T and B cells were identified by flow cytometry using MHC tetramers.
Results: We found that post-partum mice developed fetus-specific serum IgG1 and IgG2c and fetus-specific IgG-secreting cells in the spleen and bone marrow. The numbers of fetus-specific B cells increased in uterus-draining lymph nodes. To test if fetal MHC-specific memory B cells formed during pregnancy, post-partum mice were challenged with 2W-B/c splenocytes (s.c.), and MHC-specific antibody responses were measured using beads coated with BALB/c MHC class I (Kd) or class II (IEd). Mice mated with allogeneic 2W-B/c males exhibited a more rapid and robust MHC-specific antibody response than mice mated with syngeneic (B6) males, confirming that exposure to fetal antigens during pregnancy elicits the formation of MHC-specific memory.
Conclusion: These results demonstrate that semi-allogeneic pregnancy sensitizes the maternal immune system to fetal antigens, resulting in the generation of fetus-specific IgG-producing cells and memory B cells despite tolerogenic T cell responses to the fetus. We are investigating the nature of the help provided by CD4+ T cells to fetus-specific B cells and the quality of the memory B cells generated by pregnancy.
