Impact of aging on dendritic cell functions in humans

Abstract

Aging is a paradox of reduced immunity and chronic inflammation. Dendritic cells are central orchestrators of the immune response with a key role in the generation of immunity and maintenance of tolerance. The functions of DCs are compromised with age. There is no major effect on the numbers and phenotype of DC subsets in aged subjects; nevertheless, their capacity to phagocytose antigens and migrate is impaired with age. There is aberrant cytokine secretion by various DC subsets with CDCs secreting increased basal level of pro-inflammatory cytokines but the response on stimulation to foreign antigens is decreased. In contrast, the response to self-antigens is increased suggesting erosion of peripheral self tolerance. PDC subset also secretes reduced IFN-α in response to viruses. The capacity of DCs to prime T cell responses is also affected. Aging thus has a profound affect on DC functions. Present review summarizes the effect of advancing age on DC functions in humans in the context of both immunity and tolerance.

Figure 1. Increased response to self DNA in DCs from aged leads to loss of peripheral self tolerance and inflammation

Defective clearance of apoptotic cells in aged leads to accumulation of late apoptotic, secondary necrotic cells which lyse to release DNA and other self antigens that are taken up by DCs along with other cell debris leading to their maturation and cytokine secretion. These DCs can prime T and B lymphocytes resulting in their activation and proliferation. The net outcome is loss of tolerance along with increased inflammation and autoantibody production.

Figure 2. Age-associated alterations in signaling pathways in DCs impacting their functions

A. Pathogens: Figure depicts age-associated changes in signaling mechanisms leading to increased cytokine secretion in response to pathogens and decreased phagocytosis and migration of DCs. Increased basal expression of PTEN results in inhibition of activation of AKT kinase of PI3kinase signaling pathway. Reduced AKT phosphorylation functions as a positive regulator for TLR signaling leading to increased activation of p38 MAP kinase and NFκB which in turn result in increased proinflammatory cytokine secretion and inflammation. Reduced activation of AKT however inhibits phagocytosis and migration of DCs. B. Self Antigens: Figure depicts age-associated changes in signaling mechanisms leading to increased reactivity of DCs to self- antigens such as DNA. Increased basal level activation of NFκB leads to semi-maturation of DCs which results in enhanced response to self antigens and subsequent inflammation.