gms | German Medical Science

Objectives: Geriatric patients are at increased risk for nosocomial infections after trauma or surgery. CD56^bright natural killer (NK) cells play an important role in the defense against infections, as they produce interferon (IFN)-γ in response to interleukin (IL)-12 to further activate other immune cells for enhanced pathogen killing. The function of NK cells relies on cellular metabolism that is regulated by the "mechanistic target of Rapamycin" (mTOR). In young, healthy individuals, the uptake of branched chain amino acids, such as Leucine, occurs through its transporter CD98 and promotes the activation of CD56^bright NK cells through mTOR. These mechanisms can be up- or downregulated by circulating factors and cytokines. While IL-15 increases metabolic processes and activates mTOR, growth and differentiation factor (GDF)-15, using the TGF-ß pathway, can inhibit NK cells. Considering the increased risk for infection, we hypothesized a disturbed function and expression of molecules related to the metabolism of CD56^bright NK cells in ageing and after trauma. Potential approaches to restore NK cell function were addressed.

Methods: Blood samples were collected from geriatric patients (>65 y) with a fracture of the femoral neck (n=17) immediately after hospital admission and on day 1 post-surgery. Geriatric (n=11) and young individuals (18-48 y; n=11) served as controls. Participants with pre-existing immune deficiency or recent injuries were excluded. PBMCs were isolated from whole blood through density gradient centrifugation and exposed to heat inactivated Staphylococcus aureus to mimic an opportunistic infection. Some cells were moreover treated with IL-15, SB431542 (inhibition of the TGF-ß receptor) or a combination of both. The expression of IFN-γand the IL-12 receptor, as well as mTOR and CD98 was analyzed through flow cytometry. Serum samples from all cohorts were collected for GDF-15 ELISA.

Results and conclusion: CD56^bright NK cells of aged controls were impaired in IL-12R expression and IFN-γsynthesis in response to S. aureus that is associated with high levels of circulating GDF-15 and low expression of CD98. Blocking the receptor used by GDF-15 with SB431542 partially restored the IFN-γproduction. IL-15 increased the expression of CD98 and caused increased mTOR activity and IFN-γsynthesis. IL-15 synergized with SB431542. In comparison with aged controls, geriatric trauma further depressed the IFN-γproduction and IL-12R expression but did not affect CD98 and mTOR expression. IL-15 failed to increase the expression of CD98 and mTOR. Only IL-15 in combination with SB431542, but not the single components, slightly increased the IFN-γsynthesis. Thus, the function of NK cells is depressed in the elderly presumably due to circulating GDF-15 and reduced amino acid uptake, but can be improved by IL-15. Trauma further aggravates CD56^bright NK cell dysfunction and induces insensitivity to IL-15 and thereby might contribute to the enhanced risk for opportunistic infections.