Transient antibody targeting of CD45RC induces transplant tolerance and sustained antigen-specific regulatory T cells

Rat and human CD4+ and CD8+ Tregs expressing low levels of CD45RC have strong immunoregulatory properties. We describe here that human CD45 isoforms are non-redundant and identify distinct subsets of cells. We show that CD45RC is not expressed by CD4+ and CD8+Foxp3+ Tregs, while CD45RA/RB/RO are. Transient administration of monoclonal antibody (MAb) targeting CD45RC in a rat cardiac allotransplantation model induces transplant tolerance associated to inhibition of allogeneic humoral responses, but maintained primary and memory responses against cognate antigens. Anti-CD45RC MAb induces rapid death of CD45RC+ T cells through intrinsic cell signaling but preserved and potentiated CD4+ and CD8+CD45RClow/- Tregs, able to adoptively transfer donor-specific tolerance to grafted recipients. Anti-CD45RC treatment results in distinct transcriptional signature of CD4+ and CD8+CD45RClow/- Tregs. Finally, we demonstrate that anti-human CD45RC treatment inhibited graft-versus-host-disease (GVHD) in immune-humanized NSG mice. Thus, short-term anti-CD45RC is a potent novel therapeutic candidate to induce transplantation tolerance in human.