Induction of CD4+ CD25+ Foxp3+ T regulatory cells by dendritic cells derived from ILT3 lentivirus-transduced human CD34+ cells

Abstract

Immunoglobulin-like transcript 3 (ILT3) belongs to a family of inhibitory receptors with cytoplasmic immunoreceptor tyrosine based inhibitory motifs (ITIMs). Numerous studies have reported that increased ILT3 expression is associated with the tolerogenic properties of antigen-presenting cells (APCs) including dendritic cells (DCs). In this study, human CD34(+) hematopoietic stem/progenitor cells (HPSCs) were transduced with self-inactivating lentiviral vector carrying the ILT3 gene, and then induced to differentiate into DCs. Long-term and sustained transgene expression were observed. Importantly, DCs differentiated from ILT3-transduced HPSCs expressed high levels of human ILT3 and acquired strong tolerogenic capacity. This effect was associated with markedly decreased expression of co-stimulatory molecules (CD80, CD86) and down-regulation of NF-κB. Functionally, ILT3(high) DCs showed a reduced capacity to stimulate allogeneic T cell proliferation and increased the production of CD4(+)CD25(+)Foxp3(+) T regulatory cells with immunosuppressive activity. These results demonstrate that DCs derived from ILT3-transduced human CD34(+)HPSCs display tolerogenic properties to induce T regulatory cells in vitro.