Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4⁺ T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4⁺ T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4⁺CTLA4^hi, but not CD4⁺CTLA4^med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4⁺CTLA4^hi, but not CD4⁺CTLA4^med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4⁺CTLA4^hi/CD4⁺CTLA4^med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4⁺CTLA4^hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4⁺CTLA4^hi/CD4⁺CTLA4^med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4⁺CTLA4^hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

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