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Ability of Mature Dendritic Cells to Interact with Regulatory T Cells Is Imprinted during Maturation

Departments of ¹ Surgery, ² Infectious Diseases and Microbiology, and ³ Immunology, University of Pittsburgh; ⁴ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Pawel Kalinski, Department of Surgery, University of Pittsburgh, Hillman Cancer Center, UPCI Research Pavilion, Room 1.46b, 5117 Center Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-7712; Fax: 412-623-7713; E-mail: kalinskip{at}upmc.edu.

Key Words: chemokines • CCL5 • CCL22 • CXCL10 • CCR4 • CXCR3 • PGE₂ • IFN • T cells • effector T cells • CTLs • Th1 cells • Treg cells • dendritic cells • cancer vaccines

Preferential activation of regulatory T (Treg) cells limits autoimmune tissue damage during chronic immune responses but can also facilitate tumor growth. Here, we show that tissue-produced inflammatory mediators prime maturing dendritic cells (DC) for the differential ability of attracting anti-inflammatory Treg cells. Our data show that prostaglandin E₂ (PGE₂), a factor overproduced in chronic inflammation and cancer, induces stable Treg-attracting properties in maturing DC, mediated by CCL22. The elevated production of CCL22 by PGE₂-matured DC persists after the removal of PGE₂ and is further elevated after secondary stimulation of DC in a neutral environment. This PGE₂-induced overproduction of CCL22 and the resulting attraction of FOXP3⁺ Tregs are counteracted by IFN, a mediator of acute inflammation, which also restores the ability of the PGE₂-exposed DC to secrete the Th1-attracting chemokines: CXCL9, CXCL10, CXCL11, and CCL5. In accordance with these observations, different DCs clinically used as cancer vaccines show different Treg-recruiting abilities, with PGE₂-matured DC, but not type 1–polarized DC, generated in the presence of type I and type II IFNs, showing high Treg-attracting activity. The current data, showing that the ability of mature DC to interact with Treg cells is predetermined at the stage of DC maturation, pave the way to preferentially target the regulatory versus proinflammatory T cells in autoimmunity and transplantation, as opposed to intracellular infections and cancer. [Cancer Res 2008;68(14):5972–8]

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