pathogen clearance, anti-inflammatory macrophages help clear apoptotic and necrotic debris and secrete cytokines and growth factors that promote tissue repair and regeneration. Mouse studies have shown the large variety of functions carried out by macrophages reflects the existence of multiple subsets and lineages of macrophages, each occupying distinct niches within tissues. For example, resident macrophages have recently been reported to interact directly with the nervous system in the intestine [28] and adipose tissue [29, 30] to regulate tissue function. Taken together, these data indicate macrophages have a central role in maintaining tissue homeostasis and also orchestrating immune responses.
Despite this importance, relatively little is known about changes in tissue macrophage function during aging, largely due to their poor accessibility within tissues. Monocyte-derived macrophages from human elderly human blood donors show impaired DC-SIGN-induced reduction in the expression of TLR3 following infection with West Nile virus (WNV) in vitro [31]. This impairment via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway may be relevant for elevated cytokine production contributing to permeability of the blood-brain barrier and increased severity of WNV infection in older individuals [31, 32]. Murine studies also support an age-related increase in influenza A virus (IAV) susceptibility that may contribute to impaired tissue repair and altered cytokine dynamics [33–35]. In aged mice, elicited peritoneal macrophages showed reduced phagocytosis of FITC-labeled Escherichia coli [36]. Importantly, this same study found in vitro differentiated bone marrow-derived macrophages from old mice did not have this defect, suggesting mechanisms beyond cell-intrinsic changes during aging. Notably, peritoneal macrophages transferred from adult into old mice lost their phagocytic capacity. This result emphasizes that the tissue environment is a critical determinant of macrophage function.
Dendritic Cells
DCs are key sources of inflammatory cytokines and costimulatory molecules that instruct the development of the adaptive antimicrobial immune response. Multiple classes of DCs exist, with the most common being myeloid DCs (mDCs) that activate naïve T cells, and plasmacytoid DCs (pDCs) which are major sources of IFNα following viral infection. DCs reside within lymph nodes or other tissues and survey the local microenvironment and then migrate to nearby lymph nodes that are being patrolled by adaptive immune cells. Recent studies using a unique resource of tissue acquisition from human organ donors have revealed that DC subset composition varies by tissue and age in humans, and these changes may impact site-specific immunity [37]. Both mDCs and pDCs from older donors show lower expression of TLRs globally and substantial decreases in cytokine production following TLR stimulation [38, 39]. Recent studies of DCs detected lower levels of RIG-I from older human subjects [40]. Similarly, pDCs and monocyte-derived DCs from healthy older subjects also secrete less IFN in response to IAV [41–43] and to WNV [38, 40]. DC production of type I IFN was significantly lower in older donors compared to younger donors, with diminished induction of late phase signaling responses, e.g. STAT1, IRF7, and IRF1, suggesting defective regulation of type I IFN induction [40]. IFN production by pDCs is decreased in older HSV-2-infected mice owing to impaired IRF7 upregulation upon viral infection, potentially further compromising antiviral immunity [44]. Multiple functional defects in these critical cells that bridge the innate and adaptive immune responses greatly contribute to impaired immune activation and responsiveness to infection in the elderly.
Inflammation and Innate Immunity
While most vaccine responses are assessed by generation of antigen-specific memory T cells and protective antibody titers, proper activation of the innate immune system is essential for orchestrating this process. Innate immune cells create local cytokine and chemokine gradients to recruit cells to sites of damage or infection. They also carry antigen back to lymph nodes to initiate adaptive immune cell activation and expansion. During aging, many of these critical functions performed by innate immune cells become compromised, leading to poor overall immune protection and vaccine responsiveness. The chronically elevated basal levels of proinflammatory cytokines in the elderly lead to impaired responsiveness of innate immune cells by raising the threshold of activation, thereby compressing the dynamic range of responsiveness. Evidence from multiple studies in old mice illustrate the role of inflammatory cytokines in impaired innate immune function during aging. Splenic macrophages isolated from old IL-6-deficient mice have restored secretion of TNFα, IL-1β, and IL-12 after ex vivo stimulation with LPS [45]. Similarly, inflammatory monocytes were found to correlate with elevated serum TNFα and interfere with bacterial clearance from the lungs of old mice, but aged TNFα-deficient mice were able to effectively clear the infection [46]. Taken together, these data support a hypothesis that continuous bathing of innate immune cells in the inflammatory milieu of the aged individual reduces the abilities of these cells to sense and respond to signals such as tissue damage, infection, or vaccination.
Influence of Tissue Milieu on Innate Immune Cell Function
Much of what is known about innate immune cell functional changes during aging has been elucidated in vitro in cells isolated from peripheral blood and do not reflect tissue milieu. Mounting a functional immune response depends not only on intrinsic responses by innate immune cells, but also their ability to communicate with the neighboring cells around them. Animal models and studies of ex vivo human tissues have provided some insights into how the tissue microenvironment significantly shapes the function and identity of its resident immune cells [37, 47–49]. Rodent studies utilizing heterochronic parabiosis, the surgical joining of a young and old animal in which a shared circulatory system develops, have revealed environmental defects in the aged animal that can be improved by exposure to circulating factors from the young animal [50]. Similarly, adoptive cell transfers of adult or old cells into reciprocally aged hosts reveal that the aged environment impairs functional responses of innate immune cells [36, 51, 52]. Although these experimental techniques are limited to inbred animal models, innovative studies in lung transplant patients have recently been used to study tissue-resident T cells in humans [53]. In the following sections, we describe selected tissues that exhibit strong age-related alterations and