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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2878-2885.
Prepublished online as a Blood First Edition Paper on July 30, 2008; DOI 10.1182/blood-2008-03-143222.


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NEOPLASIA

Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma

Kavita M. Dhodapkar1, Scott Barbuto1, Phillip Matthews2, Anjli Kukreja2, Amitabha Mazumder3, David Vesole3, Sundar Jagannath3, and Madhav V. Dhodapkar2,4,5

1 Laboratory of Cellular Physiology and Immunology and 2 Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University, New York, NY; 3 St Vincent's Cancer Center, New York, NY; 4 Section of Hematology, Yale University, New Haven, CT; and 5 Program in Hematologic Malignancies, Yale Cancer Center, New Haven, CT

IL17-producing (Th17) cells are a distinct lineage of T helper cells that regulate immunity and inflammation. The role of antigen-presenting cells in the induction of Th17 cells in humans remains to be fully defined. Here, we show that human dendritic cells (DCs) are efficient inducers of Th17 cells in culture, including antigen-specific Th17 cells. Although most freshly isolated circulating human Th17 cells secrete IL17 alone or with IL2, those induced by DCs are polyfunctional and coexpress IL17 and IFN{gamma} (Th17-1 cells). The capacity of DCs to expand Th17-1 cells is enhanced upon DC maturation, and mature DCs are superior to monocytes for the expansion of autologous Th17 cells. In myeloma, where tumors are infiltrated by DCs, Th17 cells are enriched in the bone marrow relative to circulation. Bone marrow from patients with myeloma contains a higher proportion of Th17-1 cells compared with the marrow in preneoplastic gammopathy (monoclonal gammopathy of undetermined significance [MGUS]). Uptake of apoptotic but not necrotic myeloma tumor cells by DCs leads to enhanced induction of Th17-1 cells. These data demonstrate the capacity of DCs to induce expansion of polyfunctional IL17-producing T cells in humans, and suggest a role for DCs in the enrichment of Th17-1 cells in the tumor bed.


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