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The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder.

Background/Aims: Mindfulness-based stress reduction (MBSR) has enhanced cognition, positive emotion, and immunity in younger and middle-aged samples; its benefits are less well known for older persons. Here we report on a randomized controlled trial of MBSR for older adults and its effects on executive function, left frontal asymmetry of the EEG alpha band, and antibody response. Methods: Older adults (n = 201) were randomized to MBSR or waiting list control. The outcome measures were: the Trail Making Test part B/A (Trails B/A) ratio, a measure of executive function; changes in left frontal alpha asymmetry, an indicator of positive emotions or approach motivation; depression, mindfulness, and perceived stress scores, and the immunoglobulin G response to a protein antigen, a measure of adaptive immunity. Results: MBSR participants had a lower Trails B/A ratio immediately after intervention (p < 0.05); reduced shift to rightward frontal alpha activation after intervention (p = 0.03); higher baseline antibody levels after intervention (p < 0.01), but lower antibody responses 24 weeks after antigen challenge (p < 0.04), and improved mindfulness after intervention (p = 0.023) and at 21 weeks of follow-up (p = 0.006). Conclusions: MBSR produced small but significant changes in executive function, mindfulness, and sustained left frontal alpha asymmetry. The antibody findings at follow-up were unexpected. Further study of the effects of MBSR on immune function should assess changes in antibody responses in comparison to T-cell-mediated effector functions, which decline as a function of age.

Whether graft rejection occurs by direct or indirect presentation of antigen is still controversial. However, using a mouse ear skin allograft model and a two-photon intravital imaging approach, Susanna Celli and her colleagues have been able to dissect some of the dynamic processes involved in graft rejection, including early- and late-stage events at the transplant site, as well as intermediate events in the draining lymph node. Transplant rejection involves a coordinated attack of the innate and the adaptive immune systems of the host. To investigate this dynamic process and the contributions of both donor and host cells, we developed an ear skin graft model suitable for intravital imaging. We found that donor dermal dendritic cells (DCs) migrated rapidly from the graft and were replaced by host CD11b + mononuclear cells. The infiltrating host cells captured donor antigen, reached the draining lymph node and cross-primed graft-reactive CD8 + T cells. Furthermore, we defined the mechanisms by which host T cells target graft cells. We found that primed T cells entered the graft from the surrounding tissue and localized selectively at the dermis-epidermis junction. Later, CD8 + T cells disseminated throughout the graft and many became arrested. These results provide insights into the antigen presentation pathway and the stepwise progression of CD8 + T cell activity, thereby offering a framework for evaluating how immunotherapy might abrogate the key steps in allograft rejection.

Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. In an effort to determine the optimal way to strengthen immune defenses, 28 clinical stage I–II melanoma patients were randomized in a 3-arm Phase II study to receive, prior to excision and sampling of the SLN, i.d. injections of saline or low-dose CpG-B (CpG), alone or combined with GM-CSF (GM), around the melanoma excision site. We previously described the combined administration of these DC-targeting agents to result in activation and recruitment of potentially cross-presenting BDCA3 + DCs to the SLN. In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8 + T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG ± GM-administered patients showed significantly lower numbers of SLN metastases (saline: 4/9, CpG + GM: 1/9, CpG: 0/10, p  = 0.04). These findings indicate that i.d. delivery of low-dose CpG ± GM potentially arms the SLN of early-stage melanoma patients against metastatic spread, but that antitumor efficacy may be further boosted by counteracting the collateral activation of Tregs.

The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18–20 months after their last dose (at about 3.5 years of age). We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%–100% against matched strains, 60%–100% against mismatched strains) or at 40 and 42 months (n = 29) (31%–100% against matched strains, 41%–81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%–100% and against mismatched strains in 59%–100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. Trial registration:ClinicalTrials.gov, no. NCT01027351

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKT like subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection. Virginie Rozot and Elisa Nemes et al. report comprehensive profiling of immune responses from participants in a recent clinical trial of the H4:IC31 and BCG vaccines against Mycobacterium tuberculosis infection. Using a novel analysis platform, they uncover complex vaccine-induced modulation of different immune cell subsets.

Psoriasis (Ps) is a chronic, immune-mediated, skin inflammatory disease affecting up to 3% of the population worldwide. Different environmental triggers initiate this complex multifactorial syndrome. Many individuals affected by Ps (6-26%) develop inflammatory disease in other organs, often in the joints as in psoriasis arthritis (PsA). Animal models that reflect the typical Ps syndrome, including both skin and joint pathology as in Ps and PsA, are valuable tools for dissecting disease pathways leading to clinical manifestations. In this context, we developed a new acute Ps and PsA-like disease model that appears after exposure to Saccharomyces cerevisiae mannan in certain mouse strains. The disease was found to be triggered by mannan-activated macrophages, leading to the activation of a pathogenic interleukin-17 pathway involving innate lymphocytes. Interestingly, the production of reactive oxygen species protected the mice from the triggering of this pathway and ameliorated Ps and PsA development.

Key Points NF-κB (nuclear factor-κB) activation is mediated by two main signalling pathways, the canonical and non-canonical pathways, which differ in both signalling mechanisms and biological functions. The canonical NF-κB pathway is stimulated by ligands of diverse immune receptors and involves the rapid and transient activation of IκB kinase (IKK), IKK-mediated IκBα phosphorylation, and subsequent IκBα degradation and nuclear translocation of canonical NF-κB members, including p50, RELA and c-REL. The non-canonical NF-κB pathway selectively responds to signals from a subset of tumour necrosis factor receptor (TNFR) superfamily members and involves slow and persistent activation of NF-κB-inducing kinase (NIK), NIK-mediated p100 phosphorylation, and subsequent p100 processing and nuclear translocation of non-canonical NF-κB members, including p52 and RELB. The non-canonical NF-κB pathway is tightly controlled by ubiquitin-dependent degradation of NIK mediated by an E3 ubiquitin ligase complex composed of cIAP family members, TNFR-associated factor 2 (TRAF2) and TRAF3; activation of non-canonical NF-κB involves signal-induced disruption of the cIAP E3 complex, typically via degradation of TRAF3, and accumulation of NIK. The non-canonical NF-κB pathway regulates important aspects of immune functions, including lymphoid organ development, the cross-priming function of dendritic cells, B cell survival and germinal centre reactions, generation and maintenance of effector and memory T cells, and antiviral innate immunity. The non-canonical NF-κB pathway is involved in various inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, kidney inflammation and injury, metabolic inflammation, and central nervous system inflammation. Defects in the non-canonical pathway of NF-κB activation are associated with severe immune deficiencies, and aberrant activation of this pathway can cause autoimmune and inflammatory diseases. Here, the author investigates the activation, signalling mechanisms and the biological function of the non-canonical NF-κB pathway. The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.

The new vaccines against SARS-CoV-2 are novel in terms of specificity, their wide dissemination across the global population and the inclusion of newly licensed mRNA platforms. We discuss here how the approved vaccines trigger innate immunity to promote durable immunological memory and consider the future implications of protecting populations with these vaccines.This Comment outlines how the recently licensed vaccines for COVID-19 activate innate immune mechanisms to promote immune memory to SARS-CoV-2. The authors also consider future challenges that could limit vaccine efficacy.