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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.