Mechanisms of humoral sensitization to fetal antigens during pregnancy 2259768

Abstract Introduction 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. Funding Source 5R01AI182097 Topic Categories Mucosal and Regional Immunology (MUC)