Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by beta-chemokines rather than IL-12

Monocyte-derived dendritic cells (MDDCs) activate naive T lymphocytes to in duce adaptive immunity, effecting Th1 polarization through IL-12. However, little is known about other potential DC Th1 polarizing mechanisms, or how T cell polarization may be affected by DCs differentiating in, or exposed t o, a proinflammatory environment. Macrophages (M Phi s) are DC precursors a bundant in inflamed tissues, lymph nodes, and tumors. Thus we studied the T cell-activating and -polarizing properties of M Phi-derived DCs (Phi DCs). Monocytes were cultured in M Phi-CSF (M-CSF) to produce M Phi s, which wer e then differentiated into DCs following culture with GM-CSF plus IL-4, Phi DCs activated a significant allogeneic MLR and were significantly better t han MDDCs in activating T cells with superantigen, Most strikingly, Phi DCs elicited up to 9-fold more IFN-gamma from naive or Ag-specific T cells com pared with MDDCs (with equivalent IL-4 secretion), despite producing up to 9-fold less IL-12, Neutralization of MDDC, but not Phi DC IL-12 significant ly inhibited T cell IFN-gamma induction. Phi DCs produced up to 12-fold mor e beta-chemokines (macrophage-inflammatory protein-1 alpha, -1 beta, and RA NTES) than MDDCs. Ab blockade of CCR5, but not CXC chemokine receptor 4, in hibited T cell IFN-gamma induction by Phi DCs significantly greater than by MDDCs, Thus DCs differentiating from M Phi s induce T cell IFN-gamma throu gh beta-chemokines with little or no requirement for IL-12, Myeloid DCs ari sing from distinct precursor cells may have differing properties, including different mechanisms of Th1 polarization. These data are the first reports of IFN-gamma induction through chemokines by DCs.