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The measles, mumps, and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long- term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized, placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. Using single-cell RNA-Seq, we found that MMR caused transcriptomic changes in [CD14.sup.+] monocytes and NK cells, but most profoundly in [gamma][delta] T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of [gamma][delta] T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFN-[gamma], as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of [gamma][delta] T cell function induced by MMR vaccination., Introduction Vaccines are developed to target specific pathogens. However, an accumulating body of evidence suggests that certain live-attenuated vaccines provide a broad spectrum of protection against heterologous infections as well [...]

BACKGROUND. The antituberculosis vaccine bacillus Calmette-Guerin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. Eighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG. RESULTS. Compared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration. FUNDING. The Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation., Introduction The antituberculosis vaccine bacillus Calmette-Guerin (BCG) has the highest vaccine coverage worldwide (1). BCG protects primarily against disseminated tuberculosis (TB) in children (2), whereas protection against pulmonary TB in [...]

BACKGROUND. Induction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guerin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases. METHODS. We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity. RESULTS. While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination. CONCLUSION. The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications. FUNDING. Netherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation., Introduction The traditional view of vaccines is that they protect against a particular infection by induction of long-lasting specific adaptive immune memory. The discovery of the induction of nonspecific innate [...]

Atherosclerotic cardiovascular diseases (CVD) are among the leading causes of death in the world. Monocyte‐derived macrophages are key players in the pathophysiology of atherosclerosis. Innate immune memory following exposure of monocytes to atherogenic compounds, such as oxidized low‐density lipoproteins (oxLDL), termed trained immunity, can contribute to atherogenesis. The current study aimed to elucidate intracellular mechanisms of oxLDL‐induced trained immunity. Using untargeted intracellular metabolomics in isolated human primary monocytes, we show that oxLDL‐induced trained immunity results in alterations in the balance of intracellular steroid hormones in monocytes. This was reflected by a decrease in extracellular progesterone concentrations following LPS stimulation. To understand the potential effects of steroid hormones on trained immunity, monocytes were costimulated with oxLDL and the steroid hormones progesterone, hydrocortisone, dexamethasone, β‐estradiol, and dihydrotestosterone. Progesterone showed a unique ability to attenuate the enhanced TNFα and IL‐6 production following oxLDL‐induced trained immunity. Single nucleotide polymorphisms in the nuclear glucocorticoid, progesterone, and mineralocorticoid receptor were shown to correlate with ex vivo oxLDL‐induced trained immunity in 243 healthy volunteers. Pharmacologic inhibition experiments revealed that progesterone exerts the suppression of TNFα in trained immunity via the nuclear glucocorticoid and mineralocorticoid receptors. Our data show that progesterone has a unique ability to suppress oxLDL‐induced trained immunity. We hypothesize that this effect might contribute to the lower incidence of CVD in premenopausal women. [ABSTRACT FROM AUTHOR]

Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro‐induced trained immunity responses were assessed in two independent population‐based cohorts of healthy individuals, the 300 Bacillus Calmette‐Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta‐analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K‐Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec‐5 and Siglec‐14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Summary: Toll‐like receptor 10 (TLR10) is the only member of the human Toll‐like receptor family with an inhibitory function on the induction of innate immune responses and inflammation. However, its role in the modulation of trained immunity (innate immune memory) is unknown. In the present study, we assessed whether TLR10 modulates the induction of trained immunity induced by β‐glucan or bacillus Calmette–Guérin (BCG). Interleukin 10 receptor antagonist production was increased upon activation of TLR10 ex vivo after BCG vaccination, and TLR10 protein expression on monocytes was increased after BCG vaccination, whereas anti‐TLR10 antibodies did not significantly modulate β‐glucan or BCG‐induced trained immunity in vitro. A known immunomodulatory TLR10 missense single‐nucleotide polymorphism (rs11096957) influenced trained immunity responses by β‐glucan or BCG in vitro. However, the in vivo induction of trained immunity by BCG vaccination was not influenced by TLR10 polymorphisms. In conclusion, TLR10 has a limited, non‐essential impact on the induction of trained immunity in humans. [ABSTRACT FROM AUTHOR]