Altered Innate Immune Functioning of Dendritic Cells in Elderly Humans: A Role of Phosphoinositide 3-Kinase-Signaling Pathway

Abstract

Aging represents a state of paradox where chronic inflammation is associated with declining immune responses. Dendritic cells (DCs) are the major APCs responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. In this study, we have compared the innate immune functions of monocyte-derived myeloid DCs from elderly subjects with DCs from young individuals. We show that although phenotypically comparable, DCs from the aging are functionally different from DCs from the young. In contrast to DCs from the young, DCs from elderly individuals display 1) significantly reduced capacity to phagocytose Ags via macropinocytosis and endocytosis as determined by flow cytometry; 2) impaired capacity to migrate in vitro in response to the chemokines MIP-3β and stromal cell-derived factor-1; and 3) significantly increased LPS and ssRNA-induced secretion of TNF-α and IL-6, as determined by ELISA. Investigations of intracellular signaling revealed reduced phosphorylation of AKT in DCs from the aging, indirectly suggesting decreased activation of the PI3K pathway. Because the PI3K-signaling pathway plays a positive regulatory role in phagocytosis and migration, and also functions as a negative regulator of TLR signaling by inducing activation of p38 MAPK, this may explain the aberrant innate immune functioning of DCs from elderly subjects. Results from real-time PCR and protein expression by flow cytometry demonstrated an increased expression of phosphatase and tensin homolog, a negative regulator of the PI3K-signaling pathway, in DCs from the aging. Increased phosphatase and tensin homolog may thus be responsible for the defect in AKT phosphorylation and, therefore, the altered innate immune response of DCs from elderly humans.

The Influence of Age and Sex on the Cell Counts of Peripheral Blood Leukocyte Subpopulations in Chinese Rhesus Macaques

“…A phenomenon has been reported in children during the first decade of life that their pDCs numbers decline rapidly whereas the numbers of mDCs remain relatively stable (20,21). There are at least three studies demonstrated an age-related decline of pDC (22)(23)(24) but two other studies showed no changes (19,25). Conflicting findings have also been reported with regard to the age-related changes in mDCs.…”

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+T cell receptor repertoire clonality

“…2 As humans age, immune responses become impaired, characterized by (1) reduced lymphopoiesis of new na€ ıve B and T cells, with novel BCRs 6 and TCRs, 7 respectively, (2) reduced dendritic cell (DC) function resulting in poor responses to inflammatory signals and lowered capacity to present antigen and to activate adaptive immune responses, 8 (3) poor germinal center formation, site of B cell expansion and selection, 9 and (4) decreased potential for T cell expansion, expression of activation markers, production of cytokines, diversity of TCR repertoire and delayed T cell responses to antigen. 7,10 Thus, these changes during aging help to explain the increased susceptibility to infection and reduced response to vaccinations in the elderly population.…”

The Innate Immune System and Aging: What is the Contribution to Immunosenescence ?

“…Thus, the alteration of the innate immune response to influenza infection is largely contributing to the pathogenesis of influenza virus besides the well-known role of the adaptive immune response [22]. DC appear to be altered not only in their basic functions such as phagocytosis, chemotaxis and production of IL-12, but also in their ability to activate naïve CD4+ T cells via antigen presentation [63,72] and this has been attributed to decreased PI3K activity [73]. Reduced PI3K was implicated in both age-related reduced DC migration and also as a negative regulator of TLR signalling.…”

“…• Chemotaxis decreased or no change [15,16,17] Free radical production decrease [15,16,17] Intracellular killing decreased [15,16,17] Rescue from apoptosis decreased [18] Intracellular signalling altered [14,19,20 Free radical production decrease [56] Intracellular killing decrease [56] Pro-inflammatory cytokine production increased [47,48,54,57] Intracellular signalling altered [29,47,48,49] Dendritic cells Phenotype no change or decrease [47,63,64] Subpopulations no change [63,64] Receptors number decrease or no change [29,65] Functions Phagocytosis decrease or no change [63,72,73] Antigen presentation decreased [63,72] Chemotaxis decreased [73] Intracellular killing decrease [63] Pro-inflammatory cytokine production increased [63,66,68] T cell priming altered [63,72] Cytokine production decreased or no change [84,88] T cell priming altered …”