Maternal Dendritic Cells Influence Fetal Allograft Response and Tolerance

Abstract

Intrauterine hematopoietic cell transplantation (IUT), a promising therapy for congenital haematological disease, is limited by subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into fetal IUT recipients may directly influence immune-mediated donor cell clearance. We investigated if maternal dendritic cell (DC) suppression reduces recipient alloresponsiveness to donor cells, improving DCC. IUT was performed at E14 in pregnancies resulting from crossing CD11c.DTR(B6) females and Balb/c males, with semiallogenic Balb/c or C57BL/6, or fully allogenic C3H donor cells, 24h after administering diphtheria toxin to the dam, transiently suppressing maternal DC. This resulted in reduced MMc in recipient fetuses, greatest after Balb/c transplantation, also associated with the highest DCC, and lowest with C3H. Maternal-derived T-cell receptor (TCR) clonotypes were enriched in IUT recipients and displayed substantially reduced diversity. Recipient pups with reduced MMc increased expression of regulatory T-cell subtypes, reduced expression of proinflammatory cytokines, and demonstrated enhanced TCR clonotype diversity. DCC was primarily related to donor cell type and not influenced by MMc. Our data indicate that donor cell origin and MMc are distinct factors determining IUT effectiveness. MMc independently influences DCC and recipient tolerance to donor cells and may present novel therapeutic targets to improve transplantation outcomes.