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

Abstract

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-α 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-α 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.

Effects of aging on human leukocytes (part II): immunophenotyping of adaptive immune B and T cell subsets

“…Several reports have demonstrated that the fraction and number of peripheral and tissue-located Tregs increase with age (Gregg et al 2005;Vukmanovic-Stejic et al 2006;Lages et al 2008;Agius et al 2009;Booth et al 2010). Similar to the entire CD4 + T cell population, the fraction of regulatory recent thymic emigrants and Tregs with a naïve phenotype decreases with increasing Tregs with a memory phenotype (Gregg et al 2005;Booth et al 2010).…”

“…This T cell subset is less well studied than T and B cells, but similarities to what is known for αβTCR + T cells remain clear: the repertoire of γδTCR + T cells and the cell counts decrease with age (Giachino et al 1994;Colonna-Romano et al 2002;Argentati et al 2002;Re et al 2005;Andreu-Ballester et al 2012). The Treg population increases with age (Gregg et al 2005;Vukmanovic-Stejic et al 2006;Lages et al 2008;Agius et al 2009;Booth et al 2010), although the internal composition changes from a naïve to a memory phenotype (Gregg et al 2005;Booth et al 2010).…”

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

“…18,20,21,44,45 In addition, decreased macrophage TNF is critical in aging-associated immunity deficiency. 46 These studies highlight the essential role of TNF in human immunophysiology. Furthermore, using TNF to kill tumor cells has been proposed in cancer treatment 47 ; and exciting positive results have been reported in an animal model.…”

“…In healthy, noninflamed individuals, SMT may boost immune surveillance via enhanced macrophage TNF production (Figs 2 and 3). 9,35,46 This uses the beneficial feature of physiological TNF and may be one of the reasons why SMT is effective during wellness management for rather healthy individuals. 4 In inflammatory pain conditions, the early TNF spike produced by SMT may serve as a fresh stimulus, sensitizing and activating Tregs to the chronically high level of TNF.…”

Superior Sensitivity of Ex Vivo IFN-γ Release Assays as Compared to Skin Testing in Immunocompromised Patients

“…This may, on one hand, be due to the fact that the formation of a skin test induration not only depends on the functionality of antigen-specific cells but also on their ability to be actively recruited to the injection site, which is defined by the local tissue environment (17). Both processes are known to be negatively affected by immunosuppressive drugs.…”