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ORIGINAL RESEARCH ARTICLE

Cross-Linking Cell Surface Chemokine Receptors Leads to Isolation, Activation, and Differentiation of Monocytes into Potent Dendritic Cells

Fumikazu Nimura^*,, Li Feng Zhang^*, Kazu Okuma^*, Reiko Tanaka^*, Hajime Sunakawa, Naoki Yamamoto and Yuetsu Tanaka^*,1

^* Department of Immunology and Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan; and AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan

To whom requests for reprints should be addressed at ¹ Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan. E-mail: yuetsu{at}s4.dion.ne.jp

Monocytes express on the cell surface several kinds of chemokine receptors that facilitate chemotaxis followed by differentiation in target tissues. In the present study, we found that a large number of monocytes from peripheral blood mononuclear cells (PBMCs) tightly adhered to plastic cell culture plates precoated with a monoclonal antibody (mAb, clone T312) specific for human CCR5 but not an isotype control after overnight incubation. Soluble T312 did not induce such adhesion, indicating that cross-linking of CCR5 is required for the enhanced adhesion of monocytes. The adhesion was blocked by a PI3-K inhibitor and an anti-CD18 blocking mAb. Following the cross-linking of CCR5, monocytes synthesized high levels of M-CSF, RANTES, MIP-1, and MIP-1ß associated with a readily detectable downmodulation of CD14, CD4, CCR5, and CXCR4 expression. The T312-enriched monocytes differentiated into dendritic cells (DCs) in the presence of interleukin-4 alone. After maturation with ß-interferon, the T312-induced DCs stimulated proliferation of allogeneic naïve CD4⁺ T cells accompanied by the synthesis of high levels of -interferon in vitro. Furthermore, the T312-induced DCs were capable of stimulating antigen-specific human T- and B-cell immune responses in our hu-PBL-SCID mouse system. Finally, screening of other anti-chemokine receptor mAbs showed that select clones of mAbs against CXCR4 and CCR3 were also capable of facilitating enrichment of monocytes similar to T312. These results show that cross-linking of chemokine receptors on monocytes by appropriate mAbs leads to activation and differentiation of monocytes and that the method described herein provides an alternate simple strategy for adherence-based isolation of monocytes and generation of functional DCs.

Key Words: dendritic cell • monocyte • chemokine receptor • human immunodeficiency virus (HIV)

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