Innate Immune Function by Toll-like Receptors: Distinct Responses in Newborns and the Elderly

Abstract

Summary Given the "inborn" nature of the innate immune system, it is surprising to find that innate immune function does in fact change with age. Similar patterns of distinct Toll-like receptor (TLR)-mediated immune responses come to light when one contrasts innate immune development at the beginning of life with that toward the end of life. Importantly, these developmental patterns of innate cytokine responses correlate with clinical patterns of susceptibility to disease: A heightened risk of suffering from excessive inflammation is often detected in prematurely born infants, disappears over the first few months of life, and reappears toward the end of life. In addition, risk periods for particular infections in early life reemerge in older adults. The near-mirror-image patterns that emerge in contrasts of early versus late innate immune ontogeny emphasize changes in host-environment interactions as the underlying molecular and teleologic drivers.

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…Indeed, one of the last cytokines to reach adult levels after birth is the Th1-promoting cytokine IL-12 (IL-12p70) (27). Originally proposed as a hypothesis by Adrian Hayday (1), there is increasing evidence, including our own results, that γδ T cells are important in early life (28)(29)(30)(31)(32)(33).…”

“…4A) and HMB-PP ( (41). High expression of the IL-18 receptor (IL-18R) (see below) on fetal Vγ9Vδ2 T cells could contribute to this expansion and might make this subset more receptive to IL-18 in early life (27). Flow cytometry data on γδ subset percentages of γδ + CD3 + lymphocytes for one fetus from which we obtained blood both at 23w5d and at 39w5d gestation; these data are representative fo the data for three different fetuses from which blood samples were derived at two different gestational times; in the lower panel, the gate is put on γδ + CD3 + lymphocytes.…”

Vaccination and heterologous immunity: educating the immune system

“…4 Antiviral cytokines, such as type I IFNs are protective in young children. For example, susceptibility to severe herpes simplex virus (HSV) infection correlates with low TLR-mediated type I IFN production in children 5 In addition to the direct antiviral mechanisms, inflammatory cytokines triggered through innate receptors also control the differentiation of the adaptive immune response and memory development. Direct effects of type I IFN are required for CD8 T cell expansion during lymphocytic choriomeningitis virus (LCMV) infection in mice, as IFNa receptor-deficient CD8 T cells have decreased survival and limited effector functions.…”

Extracellular Nucleotide Catabolism by the Group B Streptococcus Ectonucleotidase NudP Increases Bacterial Survival in Blood

“…Central to this response are host phagocytic cells, including neutrophils and macrophages, whose activities are dependent on the eATP/eAdo ratio. Moreover, innate immunity of the newborns appears polarized toward an anti-inflammatory response due, at least in part, to an elevated eAdo concentration in the cord and neonate bloods (27)(28)(29)(30). Given the putative large effects of the eATP/eAdo ratio on the control of bacterial infections, we studied the GBS ecto-5Ј-nucleoside diphosphate phosphohydrolase (NudP), which was previously identified as one of the major immunoreactive proteins during bovine mastitis (31).…”