The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20090896
The Journal of Experimental Medicine, Vol. 206, No. 9, 1929-1940
The Rockefeller University Press, 0022-1007 $30.00
© Agius et al.
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ARTICLE

 Decreased TNF-{alpha} synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging

Elaine Agius1,2, Katie E. Lacy1,2, Milica Vukmanovic-Stejic1, Ann L. Jagger3, Anna-Pia Papageorgiou4, Sue Hall5, John R. Reed1,2, S. John Curnow6, Judilyn Fuentes-Duculan7, Christopher D. Buckley6, Mike Salmon6, Leonie S. Taams3, James Krueger7, John Greenwood4, Nigel Klein5, Malcolm H.A. Rustin2, and Arne N. Akbar1

1 Department of Immunology, Division of Infection and Immunity, University College London, London, W1T 4JF, England, UK
2 Department of Dermatology, Royal Free Hospital, London, NW3 2QG, England, UK
3 Department of Immunobiology, Division of Immunology, Infection and Inflammatory Disease, King's College London School of Medicine at Guy's, King's College and St. Thomas' Hospitals, London, SE1 9RT, England, UK
4 Department of Cell Biology, Institute of Ophthalmology, University College London, London, EC1V 9EL, England, UK
5 Infectious Diseases and Microbiology Unit, Institute of Child Health, and Division of Infection and Immunity, University College London, London, WC1N 1EH, England, UK
6 Medical Research Council Centre of Immune Regulation, Division of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Edgbaston, B15 2TT, England, UK
7 Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY 10021

CORRESPONDENCE Arne N. Akbar: a.akbar{at}ucl.ac.uk

Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4+ T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-{alpha} secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-{alpha} after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging.

E. Agius, K. Lacy, and M. Vukmanovic-Stejic contributed equally to this paper.

Abbreviations used: CCR, CC chemokine receptor; CLA, cutaneous lymphocyte-associated antigen; DTH, delayed type hypersensitivity; HDMEC, human dermal microvascular endothelial cell; ICAM-1, intercellular adhesion molecule-1; Pam3CSK4, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Serl-[S]-Lys(4) trihydrochloride; PPD, purified protein derivative; VCAM-1, vascular cell adhesion molecule-1; VZV, varicella-zoster virus.

© 2009 Agius et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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