how these might impact innate immunity and vaccine efficacy.
Skin
The skin is the largest organ in the human body and represents one of the first physical barriers to protect against pathogens. Skin also contains a unique composition of innate immune cells, including macrophages, innate-like γδ T cells, as well as classical memory αβ T cells, and a specialized subset of DCs called Langerhans cells. While obvious physical appearance reflects important cellular and tissue organizational changes in aged skin, we lack a detailed understanding of how the immune system in skin changes with age. To address this gap, sophisticated methods have been developed by Dr. Arne Akbar and colleagues in which a suction blister is used to collect leukocytes and fluid from the skin after cutaneous antigen challenge. They found impaired memory T cell migration to the skin after challenge with fungal (Candida albicans), viral (varicella zoster virus, VZV), and mycobacterial (tuberculin PPD) antigen challenges. They further showed with the C. albicans model that impaired memory CD4 T cell homing to aged skin is due to reduced TNFα secretion from macrophages [54]. The reduced TNFα led to impaired endothelial activation of selectin molecules including E-selectin, VCAM-1, and ICAM-1. Ultimately, the lower adhesion molecule expression on the endothelium led to reduced memory CD4 T cell migration to the skin. Importantly, the defects in both the endothelium and macrophages could be restored in vitro, suggesting they reflect the influence of the tissue environment within the skin and may be reversible.
Skin biopsies from elderly individuals exhibit elevated p38 MAPK transcriptional signatures that correlated with impaired VZV skin response. Treating these subjects with an oral MAPK inhibitor prior to antigen challenge improves systemic inflammation and their VZV-specific recall response in the skin [55]. Similar depressed immune responses have been reported in a murine skin infection model of Staphylococcus aureus in which old mice have delayed bacterial clearance, delayed wound closure, and reduced neutrophil chemotaxis to the wound site [56]. This highlights the detrimental effects of elevated basal inflammation that compresses the dynamic range of innate immune activation in the elderly. Improving immunity in aging skin has potentially enormous clinical implications particularly as skin is a common vaccination site. Perhaps improving immune cell recruitment to and from the skin and draining lymph nodes represents a realistic approach towards achieving the goal of improved vaccine efficacy in the elderly.
Lung
Like the skin, the lung is another barrier tissue constantly exposed to environmental and microbial pathogens. Individuals aged 75–84 have nearly 20-times higher morbidity and mortality compared to younger adults after acute lung injury [57]. People over age 65 account for 70% of influenza- and pneumonia-related hospitalizations [58], and studies in mice show that aging increases susceptibility to secondary bacterial challenges after influenza infection [59]. Together, these studies highlight multiple defects in the aging lung, including local immune responsiveness and tissue maintenance and repair, which increases host vulnerability to lung damage and disease. Age-related changes in the lung milieu are significant given that even in young animals the lung environment strongly regulates the activation and function of resident immune cells [60]. In a prospective study of emergency room patients with burn inhalation injuries, older patients were at increased risk of death after burn injury and had higher concentrations of inflammatory cytokines in their serum and bronchoalveolar lavage fluid [61]. High vascularization within the lung makes it a unique site that can be rapidly infiltrated by circulating leukocytes. Increased neutrophil infiltration and activation is associated with excess immune pathology during infection in mouse and human studies [25, 62–66]. As described above, dysregulation of neutrophil responses and impaired chemotaxis could impair pathogen clearance and prolong detrimental inflammatory responses in the lungs of elderly individuals.
Lymph Node
Lymph nodes are the central hubs in which innate and adaptive immunity coordinate productive immune responses. They are highly organized structures strategically placed at intersections between draining lymphatics and the circulating blood vasculature. Upon encountering and processing pathogens in the periphery, innate immune cells such as DCs migrate to nearby lymph nodes. Migration of cells towards and within lymph nodes has been expertly reviewed previously [67]; resident innate immune cells, including macrophages, are poised to respond immediately in the case of pathogen entry, or relay immune information further into the lymph node. T cell and B cell zones in the inner cortex are spatially organized and surrounded by macrophages. Lymphocytes enter through high endothelial venules, guided by fibroblastic reticular cells. Here, they scan migratory DCs for cognate antigen. T and B cells that are continuously circulating and patrolling the body migrate through these lymph nodes and upon encountering a DC-presented cognate antigen, clonally expand and mount a massive and highly-specific adaptive immune response with the purpose of eradicating the microbial pathogen and generating long-lasting immunity. In order for this entire process to be successful, many coordinated events must be executed successfully.
Proper function of lymph nodes requires intense cross-talk between hematopoietic cells and the stroma. Accumulation of lipid droplets and increased fibrosis are common features of the disrupted lymph node architecture and disrupted spatial organization associated with aging [68, 69]. These structural changes not only impair physical communication between lymphocytes and the lymph node stroma, but also probably perturb the environment and disrupt normal homeostasis within the lymph node. Multiple studies have reported reduced lymphocyte cellularity of aged lymph nodes both during the basal state and during infection [52, 68, 70]. Disrupted organization of T cell and B cell zones in the aging lymph node further compounds the diminished immune response and may explain, in part, lower-magnitude T cell responses and lower antibody responses after infection or vaccination in the elderly.
Adipose Tissue
Although classically considered an energy storage organ, it is becoming increasingly clear that adipose tissue is also an immunologically responsive organ that contributes to systemic inflammation. Adipose tissue remodeling and redistribution into abdominal fat are common features of age-related adipose tissue dysfunction. Importantly, these physiological changes can occur independently of obesity. In addition to increased visceral adiposity, ectopic lipid accumulation in tissues, including bone marrow, the thymus, liver, and muscle increases during healthy aging and can upset normal tissue homeostasis [71].
As adipose tissue inappropriately accumulates in tissues and lymphoid organs, it disrupts tissue architecture, function, and perhaps essential cell-cell communication. Adipose tissue secretes cytokine-like molecules, known as adipokines, such as leptin and adiponectin that modulate immune cell function. Besides these secreted factors, the adipose tissue itself contains a unique immune phenotype [72].