The functional diversity of tissue-resident natural killer cells against infection.

For decades, studies of natural killer (NK) cells have focused on those found in peripheral blood (PBNK cells) as the prototype for NK cell biology. Only recently have researchers begun to explore the diversity of tissue-resident NK (tr-NK) cells. While tr-NK cells were initially identified from mice parabiosis and intravascular staining experiments, they can also be identified by tissue retention markers such as CD69, CD103 and others. More importantly, tr-NK cells have distinct functions compared to PBNK cells. Within the liver, there are diverse subsets of tr-NK cells expressing different combinations of tissue-retention markers and transcription factors, the clinical relevance of which are still unclear. Functionally, liver tr-NK are primed with immediate responsiveness to infection and equipped with regulatory mechanisms to prevent liver damage. When decidual NK (dNK) cells were first discovered, they were mainly characterized by their reduced cytotoxicity and functions related to placental development. Recent studies, however, revealed different mechanisms by which dNK cells prevent uterine infections. The lungs are one of the most highly exposed sites for infection due to their role in oxygen exchange. Upon influenza infection, lung tr-NK cells can degranulate and produce more inflammatory cytokines than PBNK cells. Less understood are gut tr-NK cells which were recently characterized in infants and adults for their functional differences. In this mini-review, we aim to provide a brief overview of the most recent discoveries on how several tr-NK cells are implicated in the immune response against infection.

Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model.

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.