Regulatory T cells establish and maintain chimerism after in utero hematopoietic cell transplantation (169.30)

Background: In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to treat congenital diseases and induce donor-specific tolerance. The role of regulatory T cells (Tregs) in the establishment and maintenance of chimerism after IUHCTx has not been established. We characterized the expansion of Tregs in a wildtype (wt) and antigen-specific setting after IUHCTx. Methods: We analyzed chimerism in BALB/c fetuses 5 weeks after allogeneic IUHCTx and characterized their T cell and APC subsets. To quantify antigen-specific Tregs, BALB/c cells were transplanted into T cell receptor transgenic fetuses that recognize BALB/c antigen via the direct (4C) or indirect (TCR75) pathway. Results: In wt animals, we found an equivalent percentage of Tregs among uninjected animals, chimeras, and injected non-chimeras. The percentage of activated CD44+ Tregs was significantly higher among chimeras compared to uninjected controls. APC maturation markers (B7 and CD40) were elevated in donor and host-derived pDC and B cells of chimeric animals. In both 4C and TCR75 recipients, chimeric mice showed deletion of T effector cells and expansion of Tregs in the thymus and spleen. 4C animals losing chimerism showed a decrease in the number of Tregs. Conclusions: Our data suggests that Tregs interact with both host and donor-derived APC and undergo activation. Successful Treg induction is important for establishing and maintaining chimerism after IUHCTx.