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The Journal of Immunology, 2007, 178: 85.12.
Copyright © 2007 by The American Association of Immunologists, Inc.
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85.12

Aberrant Innate Immune Functions of Dendritic Cells in Aged Humans

Anshu Agrawal, Sudhanshu Agrawal, Jia-ning Cao, Houfen Su and Sudhir Gupta

Division of Basic and Clinical Immunology, University of California, Irvine, C-240, Med/Sci-I, Irvine, CA, 92697-4069

Abstract

The molecular mechanisms underlying the chronic inflammation and reduced immunity observed during aging are not well understood. Comparison of the innate immune functions of monocyte-derived DCs from aging subjects with DCs from young individuals showed that MDDCs from aging individuals display

  1. significantly reduced capacity to capture antigens via macropinocytosis and receptor-mediated endocytosis as determined by flow cytometry;
  2. impaired capacity to migrate in vitro in response to the chemokine MIP3-beta; and
  3. significantly increased LPS induced secretion of TNF-alpha and IL-6.

Investigations of intracellular signaling revealed reduced phosphorylation of AKT in MDDCs from aging, suggesting decreased activation of PI3kinase signaling pathway. Since PI3K signaling pathway plays a positive regulatory role in phagocytosis and migration, and it also functions as a negative regulator of TLR signaling by inducing activation of p38 MAP kinase, this may explain the aberrant innate immune functioning of DCs from aged subjects. Results further revealed an increased expression of PTEN, a negative regulator of PI3Kinase signaling pathway, in MDDCs from aged subjects. Increased PTEN may thus be responsible for the defect in AKT phosphorylation and therefore, altered innate immune response of DCs from aged humans.

This study is supported in part by a grant AG027512 from NIH and partly by new scholar grant from the Ellison Medical Foundation.





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