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Published online before print April 22, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1107744

Received for publication November 12, 2007.
Revised February 22, 2008.
Accepted for publication March 20, 2008.

Article

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

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

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

^@ To whom correspondence should be addressed. E-mail: catharien.hilkens{at}newcastle.ac.uk.

	Abstract

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

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