Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response.

Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2, and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were located in the medulla and conditioned medullary thymocytes. NKT2 cells were abundant in the mesenteric lymph node (LN) of BALB/c mice and produced IL-4 in the T cell zone that conditioned other lymphocytes. Intravenous injection of α-galactosylceramide activated NKT1 cells with vascular access, but not LN or thymic NKT cells, resulting in systemic interferon-γ and IL-4 production, while oral α-galactosylceramide activated NKT2 cells in the mesenteric LN, resulting in local IL-4 release. These findings indicate that the localization of iNKT cells governs their cytokine response both at steady state and upon activation.

Mental disorder and opioid overdose: a systematic review.

PURPOSE: This systematic review summarizes and presents the current state of research quantifying the relationship between mental disorder and overdose for people who use opioids. METHODS: The protocol was published in Open Science Framework. We used the PECOS framework to frame the review question. Studies published between January 1, 2000, and January 4, 2021, from North America, Europe, the United Kingdom, Australia, and New Zealand were systematically identified and screened through searching electronic databases, citations, and by contacting experts. Risk of bias assessments were performed. Data were synthesized using the lumping technique. RESULTS: Overall, 6512 records were screened and 38 were selected for inclusion. 37 of the 38 studies included in this review show a connection between at least one aspect of mental disorder and opioid overdose. The largest body of evidence exists for internalizing disorders generally and mood disorders specifically, followed by anxiety disorders, although there is also moderate evidence to support the relationship between thought disorders (e.g., schizophrenia, bipolar disorder) and opioid overdose. Moderate evidence also was found for the association between any disorder and overdose. CONCLUSION: Nearly all reviewed studies found a connection between mental disorder and overdose, and the evidence suggests that having mental disorder is associated with experiencing fatal and non-fatal opioid overdose, but causal direction remains unclear.

Progesterone-Based Contraceptives Reduce Adaptive Immune Responses and Protection against Sequential Influenza A Virus Infections.

In addition to their intended use, progesterone (P4)-based contraceptives promote anti-inflammatory immune responses, yet their effects on the outcome of infectious diseases, including influenza A virus (IAV) infection, are rarely evaluated. To evaluate their impact on immune responses to sequential IAV infections, adult female mice were treated with placebo or one of two progestins, P4 or levonorgestrel (LNG), and infected with a mouse-adapted H1N1 (maH1N1) virus. Treatment with P4 or LNG reduced morbidity but had no effect on pulmonary virus titers during primary H1N1 infection compared to placebo treatment. In serum and bronchoalveolar lavage fluid, total anti-IAV IgG and IgA titers and virus-neutralizing antibody titers but not hemagglutinin stalk antibody titers were lower in progestin-treated mice than placebo-treated mice. Females were challenged 6 weeks later with either an maH1N1 drift variant (maH1N1dv) or maH3N2 IAV. The level of protection following infection with the maH1N1dv was similar among all groups. In contrast, following challenge with maH3N2, progestin treatment reduced survival as well as the numbers and activity of H1N1- and H3N2-specific memory CD8+ T cells, including tissue-resident cells, compared with placebo treatment. In contrast to primary IAV infection, progestin treatment increased the titers of neutralizing and IgG antibodies against both challenge viruses compared with those achieved with placebo treatment. While the immunomodulatory properties of progestins protected immunologically naive female mice from the severe outcomes from IAV infection, it made them more susceptible to secondary challenge with a heterologous IAV, despite improving their antibody responses against a secondary IAV infection. Taken together, the immunomodulatory effects of progestins differentially regulate the outcome of infection depending on exposure history.IMPORTANCE The impact of hormone-based contraceptives on the outcome of infectious diseases outside the reproductive tract is rarely considered. Using a mouse model, we have made the novel observation that treatment with either progesterone or a synthetic analog found in hormonal contraceptives, levonorgestrel, impacts sequential influenza A virus infection by modulating antibody responses and decreasing the numbers and activity of memory CD8+ T cells. Progestins reduced the antibody responses during primary H1N1 virus infection but increased antibody titers following a sequential infection with either an H1N1 drift variant or an H3N2 virus. Following challenge with an H3N2 virus, female mice treated with progestins experienced greater mortality with increased pulmonary inflammation and reduced numbers and activity of CD8+ T cells. This study suggests that progestins significantly affect adaptive immune responses to influenza A virus infection, with their effect on the outcome of infection depending on exposure history.