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Published online before print April 22, 2008

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(Journal of Leukocyte Biology. 2008;84:124-133.)
© 2008 by Society for Leukocyte Biology

Differential regulation of naïve and memory CD4⁺ T cells by alternatively activated dendritic cells

Amy E. Anderson^*,1, Bethan L. Sayers^*,1, Muzlifah A. Haniffa^*,,, David J. Swan^*, Julie Diboll^*, Xiao-Nong Wang, John D. Isaacs^* and Catharien M. U. Hilkens^*,2

^* Musculoskeletal Research Group,
Hematological Sciences, and
Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

²Correspondence: Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E-mail: catharien.hilkens{at}newcastle.ac.uk

Promising immunotherapeutic tools for T cell-mediated pathologies are alternatively activated dendritic cells (aaDC), which exert their effect through the regulation and tolerization of T cells. As naïve and memory T cells have different susceptibilities to tolerogenic signals, it is important to understand the modulatory effects of aaDC on these T cell subsets. We have examined regulation of naïve and memory CD4⁺ T cells by human aaDC generated with dexamethasone, the active form of vitamin D3, 1,25-dihydroxyvitamin D3, and LPS. Although aaDC induced low, primary, allogeneic responses by naïve and memory T cells, aaDC regulated the differentiation of these T cell subsets in a distinct manner. Naïve T cells primed by aaDC retained a strong, proliferative capacity upon restimulation but were skewed toward a low IFN-/high IL-10 cytokine profile. In contrast, memory T cells primed by aaDC became hyporesponsive in terms of proliferation and cytokine production. Induction of anergy in memory T cells by aaDC was not a result of the presence of CD25^hi regulatory T cells and could be partially reversed by IL-2. Both T cell subsets acquired regulatory activity and inhibited primary CD4 and CD8 responses. Addition of exogenous IL-12p70 during T cell priming by aaDC prevented anergy induction in memory T cells and cytokine polarization in naïve T cells, indicating that the lack of IL-12p70 is a key feature of aaDC. Our finding that aaDC differentially regulate naïve and memory T cells is important for understanding and maximizing the therapeutic potential of aaDC.

Key Words: tolerance • cytokine deviation • hyporesponsiveness • immunotherapy