Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Seminal fluid histocompatibility antigens contribute to T cell priming after mating in mice (#161)

Ha M. Tran 1 , Hon Yeung (Dexter) Chan 1 , David L. Adelson 2 , Sarah A. Robertson 1
  1. The Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  2. Department of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA, Australia

At conception, the female reproductive tract is exposed to factors in seminal fluid that prime the female T cell response to initiate maternal immune tolerance towards the ensuing genetically disparate fetus. Amongst the most antigenic proteins in seminal fluid are male major histocompatibility (MHC) antigens. Interaction between these antigens and T cells is thought to affect the quality of the immune response to impact subsequent pregnancy development, but this has not been formally evaluated. Our study tests the hypothesis that disparate MHC and minor histocompatibility (MiHC) antigens both stimulate the T cell repertoire after mating, leading to improved reproductive efficiency. Using C57BL/6 female mice, we assessed fetal and placental development at 17.5 days post-coitum (dpc) following mating with males of three genotypes: BALB/c (MHC and MiHC disparate), BALB/b (MHC matched and MiHC disparate), or C57BL/6 (MHC and MiHC matched). To comprehensively analyse the T cell repertoire, we sequenced T cell receptor (TCR) gDNA from uterine-draining lymph nodes (udLNs) at 3.5 dpc from females in each mating group, with unmated C56BL/6 females as a comparison. We found that pregnancies sired by Balb/c males had a 16% increase in fetal to placental weight ratio indicative of greater placental efficiency compared to pregnancies sired by Balb/b or B6 males (n=14-16/group). This was accompanied by ~2.5-fold increased udLNs and splenic weight in females mated to Balb/c males (n=12-15/group). Genomic sequencing revealed that mice mated with Balb/c males also exhibited decreased T cell receptor diversity and increased clonal proliferation (n=3-5/group). These findings demonstrate that disparate seminal fluid histocompatibility antigens, especially MHC, contribute to the activation and expansion of a paternal antigen-specific T cell repertoire to support placental development and function. Further research is underway to investigate the underlying mechanisms and define these interactions at a higher resolution with single-cell RNA-seq.