NK cell memory and help in HIV infection

While natural killer (NK) cells are lauded for their killing effector function, they also play a critical role as immune helper cells, responding with great flexibility to environmental cues to provide subsequent alarm signals crucial for shaping and regulating the adaptive immune response. Most recently, the concept of immunological memory has been extended to NK cells, with the emergence of an inflated population of NK cells deficient in FcRg (FcRg−) described in the setting of HIV-1 infection. The physiological relevance of FcRg− NK cells, including their relationship with HIV-1-associated chronic inflammatory events, and their potential to be targeted to improve HIV-1 control, are poorly understood. Here, I present an in-depth analysis of the impact of chronic HIV-1 infection and long-term antiretroviral therapy (ART) on the phenotypic and functional character of NK cells, with particular attention directed toward characterizing FcRg− NK cells and exploring the reciprocal crosstalk between NK cells and dendritic cells (DCs) to enhance cellular-mediated immunity to HIV-1. Although NK cells are capable of providing immune help in response to innate stimuli during ART-mediated viral suppression, HIV-1 infection accelerates the expansion of highly differentiated FcRg− NK ‘effector memory’ cells with limited function. By specializing in antibody-specific responses, FcRg− NK cells compromise their responsiveness to DC-derived innate stimuli, leading to qualitative differences in their helper function and crosstalk with DCs. However, the potential exists for exploiting the inflated populations of FcRg− NK cells in chronic HIV-1 infection to facilitate the induction of DC-mediated cellular immunity to HIV-1 via broadly neutralizing HIV-1-specific monoclonal antibodies (bNAbs) due to their superior antibody-dependent reactivity. Improving our understanding of the specialized nature of FcRg− memory-like NK cells will be imperative for optimizing interventions to improve health outcomes and the effectiveness of HIV-1 therapies

Sepsis with liver dysfunction and coagulopathy predicts an inflammatory pattern of macrophage activation

BackgroundInterleukin-1 receptor antagonists can reduce mortality in septic shock patients with hepatobiliary dysfunction and disseminated intravascular coagulation (HBD + DIC), an organ failure pattern with inflammatory features consistent with macrophage activation. Identification of clinical phenotypes in sepsis may allow for improved care. We aim to describe the occurrence of HBD + DIC in a contemporary cohort of patients with sepsis and determine the association of this phenotype with known macrophage activation syndrome (MAS) biomarkers and mortality. We performed a retrospective nested case-control study in adult septic shock patients with concurrent HBD + DIC and an equal number of age-matched controls, with comparative analyses of all-cause mortality and circulating biomarkers between the groups. Multiple logistic regression explored the effect of HBD + DIC on mortality and the discriminatory power of the measured biomarkers for HBD + DIC and mortality.ResultsSix percent of septic shock patients (n = 82/1341) had HBD + DIC, which was an independent risk factor for 90-day mortality (OR = 3.1, 95% CI 1.4-7.5, p = 0.008). Relative to sepsis controls, the HBD + DIC cohort had increased levels of 21 of the 26 biomarkers related to macrophage activation (p < 0.05). This panel was predictive of both HBD + DIC (sensitivity = 82%, specificity = 84%) and mortality (sensitivity = 92%, specificity = 90%).ConclusionThe HBD + DIC phenotype identified patients with high mortality and a molecular signature resembling that of MAS. These observations suggest trials of MAS-directed therapies are warranted