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Mature Human Langerhans Cells Derived from CD34⁺ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells¹

Gudrun Ratzinger^2,3,*,, Jan Baggers^2,*,, Maria A. de Cos^4,*,, Jianda Yuan^*,, Tao Dao^*,, John L. Reagan^*,, Christian Münz^||, Glenn Heller^,¶ and James W. Young^5,*,,,¶

^* Laboratory of Cellular Immunobiology, Allogeneic Bone Marrow Transplantation and Clinical Immunology Services, Division of Hematologic Oncology, Department of Medicine, and Biostatistics Service, Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, ^¶ Weill Medical College of Cornell University, and ^|| Laboratory of Viral Immunobiology, The Rockefeller University, New York, NY 10021

The emerging heterogeneity of dendritic cells (DCs) mirrors their increasingly recognized division of labor at myriad control points in innate and acquired cellular immunity. We separately generated blood monocyte-derived DCs (moDCs), as well as Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs) from CD34⁺ hematopoietic progenitor cells. Differential expression of CD11b, CD52, CD91, and the CD1 isoforms proved useful in distinguishing these three DC types. All mature DCs uniformly expressed comparable levels of HLA-DR, CD83, CD80, and CD86, and were potent stimulators of allogeneic T cells after exposure either to recombinant human CD40L trimer or a combination of inflammatory cytokines with PGE₂. moDCs, however, required 0.5–1 log greater numbers than LCs or DDC-IDCs to stimulate comparable T cell proliferation. Only moDCs secreted the bioactive heterodimer IL-12p70, and moDCs phagocytosed significantly more dying tumor cells than did either LCs or DDC-IDCs. LCs nevertheless proved superior to moDCs and DDC-IDCs in stimulating CTL against a recall viral Ag by presenting passively loaded peptide or against tumor Ag by cross-priming autologous CD8⁺ T cells. LCs also secreted significantly more IL-15 than did either moDCs or DDC-IDCs, which is especially important to the generation of CTL. These findings merit further comparisons in clinical trials designed to determine the physiologic relevance of these distinctions in activity between LCs and other DCs.

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