Abstract
BackgroundAn efficient strategy for programing dendritic cells (DCs) for cancer immunotherapy is the optimization of their maturation so that they can efficiently stimulate cancer-specific T cell responses. Interleukin (IL)-4 has appeared as an essential cytokine, widely used in vitro with granulocyte macrophage-colony stimulating factor (GM-CSF) to differentiate monocytes into immature DCs (iDC) and to prevent macrophage formation. Conflicting data have been published regarding the effect of IL-4 on functional DC maturation. To further understand IL-4’s effects on DC maturation and function in vitro, we choose the most commonly used maturation factor tumor necrosis factor (TNF)-α.MethodsHuman monocyte-derived iDC were treated for 48 h with GM-CSF and TNF-α in the presence (IL-4+-DC) or absence (IL-4−-DC) of IL-4 and functions of both DC populations were compared.ResultsOn mixed lymphocyte reaction assay, IL-4+-DC were less potent than IL-4−-DC at inducing the proliferation of allogeneic CD4+ T cells and the proportion of activated T cells expressing CD69 and/or CD25 was smaller. Interleukin-4 reduced the cell-surface expression of TNF-α-induced DC maturation markers CD83, CD86, HLA-DR and CD25 and generated a heterogeneous population of DCs. IL-4+-DC secreted less IL-12 and more IL-10 than IL-4−-DC following activation by soluble CD40L, and IL-4+-DC-activated T cells secreted lesser amounts of T helper (Th) 1 cytokines (IL-2 and interferon-γ). Importantly, IL-4 impaired the in vitro migratory capacity of DCs in response to CCL21 and CCL19 chemokines. This effect was related to reduced expression of CCR7 at both mRNA and protein levels.ConclusionInterleukin-4 used with GM-CSF and TNF-α during the maturation of DCs in vitro impaired DC functions and disturbed the maturation effect of TNF-α. Finally, our study reinforces the view that the quality of the DC maturation stimulus, which regulates DC migration and cytokine production, may be a decisive feature of the immunogenicity of DCs.
Highlights
An efficient strategy for programing dendritic cells (DCs) for cancer immunotherapy is the optimiza‐ tion of their maturation so that they can efficiently stimulate cancer-specific T cell responses
Co-culture of IL-4−-DC with CD4+ T cells induced allogeneic T-cell proliferation that strongly increased with DC number
Our results revealed that tumor necrosis factor-α (TNF-α)-matured DCs can secrete IL-12p70 in response to soluble CD40 ligand (sCD40L) stimulation, which demonstrates that the DC were not exhausted with respect to cytokine production, as was suggested for LPS-matured DCs [34]
Summary
An efficient strategy for programing dendritic cells (DCs) for cancer immunotherapy is the optimiza‐ tion of their maturation so that they can efficiently stimulate cancer-specific T cell responses. The most widely used protocols for maturation of clinical grade monocyte-derived DC include the use of granulocyte macrophage-colony stimulating factor (GMCSF) and interleukin (IL)-4 in combination with tumor necrosis factor (TNF)-α alone or with IL-1β, IL-6 and prostaglandin (PG) E2, known as “the maturation cocktail” [9, 10]. This cocktail was challenge because of low production of IL-12p70 and the induction of Th2type immune responses. At least in mice, dendritic cells matured with TNF-α can be further activated in vitro and after subcutaneous injection in vivo a process that converts their tolerogenicity into immunogenicity [12]
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