Enhancement of Antibody-Dependent Cellular Cytotoxicity of Neonatal Cells by Interleukin-2 (IL-2) and IL-12

Abstract

Newborn infants are more susceptible to infections due in part to deficiencies in the cytotoxic functions of their lymphocytes. We investigated the ability of interleukin-2 (IL-2) and IL-12 to enhance the cytotoxicity of neonatal (cord blood) and adult mononuclear cells (MNCs) in both natural killer (NK) cell and antibody-dependent cellular cytotoxicity (ADCC) assays. The cytotoxic activity of cord blood MNCs was less than 50% that of adult MNCs in most assays prior to exposure to cytokines. Incubation with IL-2 (100 U/ml) or IL-12 (1 ng/ml) for 18 h increased the NK cell activity (using K562 target cells) of both cord blood and adult MNCs, and the combination of IL-2 and IL-12 increased cord blood cytotoxicity threefold, making the cytotoxicity of cord blood cells equivalent to that of adult cells treated with the same cytokines. In ADCC assays with chicken erythrocyte targets, the combination of IL-2 and IL-12 increased the cytotoxicities of both cord blood and adult MNCs, with greater enhancement again seen with cord blood cells. In assays with NK cell-resistant CEM cells coated with human immunodeficiency virus (HIV) gp120 antigen in the presence of hyperimmune anti-HIV immunoglobulin, ADCC of cord blood MNCs was about 50% that of adult MNCs; ADCC of cord blood MNCs increased two- to threefold with the addition of IL-2 and IL-12, whereas ADCC of adult MNCs did not increase. Incubation of cord blood cells, but not adult cells, with IL-2 or IL-12 for 1 week increased the percentage of CD16+/CD56+ cells two- to fivefold and enhanced ADCC activity. Thus, IL-2 and IL-12 greatly enhance both the NK cell and ADCC activities of neonatal MNCs and increase the number of NK cells in longer-term culture.

The newborn human NK cell repertoire is phenotypically formed but functionally reduced

“…Previous work revealed that cord blood NK cells are reduced in cytotoxicity . Our work extends these findings by measuring Granzyme B's delivery of a lethal hit to targets and cleavage of caspase‐8.…”

“…This indicates that cord blood NK cells are deficient not only in inducing a loss of membrane permeability in target cells, but also in the activation of this specific biochemical pathway. This defect can be rescued by cytokine administration , but the specific pathways compromised remain the subject of ongoing investigation. Previous studies have suggested that signaling through the activating receptor 2B4 may actually be inhibitory at the earliest stages of NK cell differentiation, due to a lack of expression of its adapter protein, known as signaling lymphocytic activation molecule associated protein (SAP) .…”

“…Functionally, cord blood NK cells are reduced in cytotoxicity when compared with adult NK cells, and this deficiency can be rescued via administration of exogenous cytokines, including IL‐2, IL‐12, IL‐15, and IL‐18 . Cytotoxicity has typically been measured by the release of 51 Cr from target cells, providing a sensitive test of membrane permeability, but not an indication of apoptotic pathway initiation.…”

“…Cytotoxicity has typically been measured by the release of 51 Cr from target cells, providing a sensitive test of membrane permeability, but not an indication of apoptotic pathway initiation. Virus‐specific responses have been tested primarily against HIV, where cord blood NK cells show reduced suppression and ADCC .…”

Difference in Response of NK Cell Activity in Newborns and Adults to IL‐2, IL‐12 and IL‐15

“…It is known that IL-2 and IL-12 enhance NK activity against virus-infected cells (1,5). It has been reported that NK cell activity against K562 or HIV-infected cells can be enhanced by treatment with IL-2 and IL-12 (21,22,26). IL-15 also enhanced the NK cell activity of cord blood (28).…”