Impact of Estrogen and Progesterone on Immune Cells and Host-Pathogen Interactions in the Lower Female Reproductive Tract.

Microbial infections are a threat to women's reproductive health. Although reproductive cycles and pregnancy are controlled by sex hormones, the impact of hormones on host-pathogen interactions and immune function in the female reproductive tract are understudied. Furthermore, the changing endocrine environment throughout pregnancy may influence how and when women are susceptible to ascending infection. Because most intrauterine microbial infections originate in the lower reproductive tract, it is vital that future studies determine how different hormonal conditions influence the lower reproductive tract's susceptibility to infection to understand temporal components of infection susceptibilities across pregnancy. These studies should also extend to nonpregnant women, as it is critical to establish how hormonal fluctuations across the menstrual cycle and hormonal contraceptives may influence disease susceptibility. This review summarizes current knowledge of how estrogen and progesterone impact vaginal and cervical mucosal immunity, barrier function, and interactions with microbial communities.

HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity.

HIV-1-negative factor (Nef) protein antagonizes serine incorporator 5 (SERINC5) by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identify cyclin K (CycK) and cyclin-dependent kinase 13 (CDK13) as a Nef-associated kinase complex. CycK/CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counteractivity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we generate chimeric proteins between CD8 and SERINC5 to study their response to Nef. Nef not only downregulates but, importantly, also binds to this chimera in an S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.

A role for TNF-α in alveolar macrophage damage-associated molecular pattern release.

Chronic beryllium disease (CBD) is a metal hypersensitivity/autoimmune disease in which damage-associated molecular patterns (DAMPs) promote a break in T cell tolerance and expansion of Be2+/self-peptide-reactive CD4+ T cells. In this study, we investigated the mechanism of cell death induced by beryllium particles in alveolar macrophages (AMs) and its impact on DAMP release. We found that phagocytosis of Be led to AM cell death independent of caspase, receptor-interacting protein kinases 1 and 3, or ROS activity. Before cell death, Be-exposed AMs secreted TNF-α that boosted intracellular stores of IL-1α followed by caspase-8-dependent fragmentation of DNA. IL-1α and nucleosomal DNA were subsequently released from AMs upon loss of plasma membrane integrity. In contrast, necrotic AMs released only unfragmented DNA and necroptotic AMs released only IL-1α. In mice exposed to Be, TNF-α promoted release of DAMPs and was required for the mobilization of immunogenic DCs, the expansion of Be-reactive CD4+ T cells, and pulmonary inflammation in a mouse model of CBD. Thus, early autocrine effects of particle-induced TNF-α on AMs led to a break in peripheral tolerance. This potentially novel mechanism may underlie the known relationship between fine particle inhalation, TNF-α, and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities.

TLR9 and IL-1R1 Promote Mobilization of Pulmonary Dendritic Cells during Beryllium Sensitization.

Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and initiate metal-specific CD4+ T cell responses. Chronic beryllium disease (CBD), a life-threatening metal-induced hypersensitivity, is driven by beryllium-specific CD4+ Th1 cells that expand in the lung-draining lymph nodes (LDLNs) after beryllium exposure (sensitization phase) and are recruited back to the lung, where they orchestrate granulomatous lung disease (elicitation phase). To understand more about how beryllium exposures impact DC function during sensitization, we examined the early events in the lung and LDLNs after pulmonary exposure to different physiochemical forms of beryllium. Exposure to soluble or crystalline forms of beryllium induced alveolar macrophage death/release of IL-1α and DNA, enhanced migration of CD80hi DCs to the LDLNs, and sensitized HLA-DP2 transgenic mice after single low-dose exposures, whereas exposures to insoluble particulate forms beryllium did not. IL-1α and DNA released by alveolar macrophages upregulated CD80 on immature BMDC via IL-1R1 and TLR9, respectively. Intrapulmonary exposure of mice to IL-1R and TLR9 agonists without beryllium was sufficient to drive accumulation of CD80hi DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80hi DCs in the LDLNs of beryllium-exposed mice. Thus, in contrast to particulate forms of beryllium, which are poor sensitizers, soluble or crystalline forms of beryllium promote death of alveolar macrophages and their release of IL-1α and DNA, which act as damage-associated molecular pattern molecules to enhance DC function during beryllium sensitization.