Submitted March 21, 2006
Accepted June 1, 2006
Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after DC injection of cytokine matured DCs in myeloma patients
Devi Banerjee, Madhav V Dhodapkar, Elyana Matayeva, Ralph M Steinman, and Kavita Dhodapkar*
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY
Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University, New York, NY
* Corresponding author; email: dhodapk{at}rockefeller.edu.
CD4+CD25+FOXP3+ regulatory T cells (Tregs) play an important role in the maintenance of immune tolerance. The mechanisms controlling the induction and maintenance of Tregs in humans need to be defined. We find that human myeloid dendritic cells (DCs) are superior to other antigen presenting cells for the maintenance of FOXP3+ Tregs in culture. Co-culture of DCs with autologous T cells leads to an increase in both the number of Tregs, as well as the expression of FOXP3 protein per cell both in healthy donors and myeloma patients. DC mediated expansion of FOXP3high Tregs is enhanced by endogenous but not exogenous IL-2, and DC-T cell contact, including the CD80/86 membrane costimulatory molecules. DCs also stimulate the formation of Tregs from CD25- T cells. The efficacy of induction of Tregs by DCs depends on the nature of the DC maturation stimulus, with inflammatory cytokine treated DCs (Cyt-DC) being the most effective Treg inducers. DCs induce Tregs using cells from both healthy donors as well as myeloma patients, and the induced T regs effectively suppress T cell responses in the mixed leukocyte reaction. A single injection of Cyt-DCs led to rapid enhancement of FOXP3+ Tregs in vivo in 3/3 myeloma patients. These data reveal a role for DCs in increasing the number of functional FOXP3high Tregs in humans.
