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Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells.

ABSTRACT: The ability of cancer vaccines to induce tumor-specific CD8+ T cells in the circulation of cancer patients has been shown to poorly correlate with their clinical effectiveness. In this study, we report that although Ags presented by different types of mature dendritic cells (DCs) are similarly effective in inducing CD8+ T cell expansion, the acquisition of CTL function and peripheral-type chemokine receptors, CCR5 and CXCR3, requires Ag presentation by a select type of DCs. Both "standard" DCs (matured in the presence of PGE2) and type 1-polarized DCs (DC1s) (matured in the presence of IFNs and TLR ligands, which prevent DCs "exhaustion") are similarly effective in inducing CD8+ T cell expansion and acquisition of CD45RO+IL-7R+IL-15R+ phenotype. However, granzyme B expression, acquisition of CTL activity, and peripheral tissue-type chemokine responsiveness are features exclusively exhibited by CD8+ T cells activated by DC1s. This advantage of DC1s was observed in polyclonally activated naive and memory CD8(+) T cells and in blood-isolated melanoma-specific CTL precursors. Our data help to explain the dissociation between the ability of cancer vaccines to induce high numbers of tumor-specific CD8+ T cells in the blood of cancer patients and their ability to promote clinical responses, providing for new strategies of cancer immunotherapy.

SUBMITTER: Watchmaker PB

PROVIDER: S-EPMC2922038 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells.

Watchmaker Payal B PB Berk Erik E Muthuswamy Ravikumar R Mailliard Robbie B RB Urban Julie A JA Kirkwood John M JM Kalinski Pawel P

Journal of immunology (Baltimore, Md. : 1950) 20091216 2

The ability of cancer vaccines to induce tumor-specific CD8+ T cells in the circulation of cancer patients has been shown to poorly correlate with their clinical effectiveness. In this study, we report that although Ags presented by different types of mature dendritic cells (DCs) are similarly effective in inducing CD8+ T cell expansion, the acquisition of CTL function and peripheral-type chemokine receptors, CCR5 and CXCR3, requires Ag presentation by a select type of DCs. Both "standard" DCs ( ...[more]

PMID: 20018619

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Project description:ObjectiveDendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3? regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGF?-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2?/?) mice had impaired DCs migration and reduced CD8?? DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2?/? mice, we tested the hypothesis that CD8?? DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8?? DCs in Ccr2?/? and SKG mice.MethodsTo examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8?? DCs.ResultsFlt3L-mediated expansion of endogenous CD8?? DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8?? DCs ameliorated arthritis in Ccr2?/? mice and enhanced TGF?1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype.ConclusionCD8?? DCs were tolerogenic to the development of arthritis. CD8?? DCs deficiency heightened the sensitivity to arthritis in Ccr2?/? mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2?/? mice was T cell-independent.

Dataset Information

Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells.

Publications

Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells.

Similar Datasets

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