Infectious diseases pose a particular risk to newborns and there is a global need to protect this vulnerable group. Because of the challenges of developing vaccines that are effective in newborns, only the hepatitis B an...Infectious diseases pose a particular risk to newborns and there is a global need to protect this vulnerable group. Because of the challenges of developing vaccines that are effective in newborns, only the hepatitis B and tuberculosis vaccines are given in the first 28 days of life, and even those vaccines are mainly only offered to high-risk groups. Maternal antibodies cross the placenta and can afford some protection to the newborn, so an alternative strategy is vaccination in pregnancy. This approach has been successfully used to protect newborns against tetanus and pertussis, and vaccines that are primarily offered to protect the mother during pregnancy, such as influenza and COVID-19 vaccines, also provide some protection to newborns. A respiratory syncytial virus vaccine has recently been approved for use in pregnancy to protect newborns, and a new vaccine that will be offered during pregnancy to prevent Group B Streptococcus infection in infants is on the horizon. Here, we discuss the current vaccines that are offered during pregnancy and to newborns, the vaccines in development for future use in these groups and the challenges that remain concerning the delivery and uptake of such vaccines.
Nat Rev Immunol
· 2025 Sep · PMID 40247006
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The cells in barrier tissues can distinguish pathogenic from commensal bacteria and target inflammatory responses only in the context of infection. As such, these cells must be able to identify pathogen infection specifi...The cells in barrier tissues can distinguish pathogenic from commensal bacteria and target inflammatory responses only in the context of infection. As such, these cells must be able to identify pathogen infection specifically and not just the presence of an infectious organism, because many innocuous bacteria express the ligands that activate innate immunity in other contexts. Unravelling the mechanisms that underly this specificity, however, is challenging. Free-living nematodes, such as Caenorhabditis elegans, are faced with a similar dilemma, as they live in microorganism-rich habitats and eat bacteria as their source of nutrition. Nematodes lost canonical mechanisms of pattern recognition during their evolution and have instead evolved mechanisms to identify specific ligands or symptoms in the host that indicate active infection with an infectious microorganism. Here we review how C. elegans surveys for these patterns of pathogenesis to activate innate immune defences. Collectively, this work demonstrates that using C. elegans as an experimental platform to study host-pathogen interactions at barrier surfaces reveals primordial and fundamentally important principles of innate immune sensing in the animal branch of the tree of life.
Nat Rev Immunol
· 2025 Aug · PMID 40240657
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Asthma and chronic rhinosinusitis (CRS) are common chronic inflammatory diseases of the respiratory tract that have increased in prevalence over the past five decades. The clinical relationship between asthma and CRS has...Asthma and chronic rhinosinusitis (CRS) are common chronic inflammatory diseases of the respiratory tract that have increased in prevalence over the past five decades. The clinical relationship between asthma and CRS has been well recognized, suggesting a common pathogenesis between these diseases. Both diseases are driven by complex airway epithelial cell and immune cell interactions that occur in response to environmental triggers such as allergens, microorganisms and irritants. Advances, including a growing understanding of the biology of the cells involved in the disease, the application of multiomics technologies and the performance of large-scale clinical studies, have led to a better understanding of the pathophysiology and heterogeneity of asthma and CRS. This research has promoted the concept that these diseases consist of several endotypes, in which airway epithelial cells, innate lymphoid cells, T cells, B cells, granulocytes and their mediators are distinctly involved in the immunopathology. Identification of the disease heterogeneity and immunological markers has also greatly improved the protocols for biologic therapies and the clinical outcomes in certain subsets of patients. However, many clinical and research questions remain. In this Review, we discuss recent advances in characterizing the immunological mechanisms of asthma and CRS, with a focus on the main cell types and molecules involved in these diseases.
CD8 T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as e...CD8 T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic viral infection. Here, we discuss the molecular and spatiotemporal mechanisms beyond exhaustion that underlie the inability of CD8 T cells to eradicate malignant or chronically infected cells. We also propose a framework to enhance our understanding of these mechanisms - which include tolerization, anergy, senescence, cell death, exclusion and ignorance - with the ultimate aim of informing novel approaches to improve the clinical management of cancer and chronic viral infection.
Regulatory T (T) cells have a central role in the maintenance of immune surveillance and tolerance. They can migrate from lymphoid organs to blood and then into tissues and egress from tissues into draining lymph nodes....Regulatory T (T) cells have a central role in the maintenance of immune surveillance and tolerance. They can migrate from lymphoid organs to blood and then into tissues and egress from tissues into draining lymph nodes. Specialized endothelial cells of blood and lymphatic vessels are the key gatekeepers for these processes. T cells that transmigrate across single-cell layers of endothelial cells engage in bidirectional crosstalk with these cells and regulate vascular permeability by promoting structural modifications of blood and lymphatic endothelial cells. In turn, blood and lymphatic endothelial cells can modulate T cell recirculation and residency. Here, we discuss recent insights into the cellular and molecular mechanisms of the crosstalk between T cells and endothelial cells and explore potential therapeutic strategies to target these interactions in autoimmunity, transplantation and cancer.
The mystery surrounding the mechanisms by which antibody diversity is generated was largely settled in the 1970s by the discoveries of variable gene rearrangements and somatic hypermutation. This led to the paradigm that...The mystery surrounding the mechanisms by which antibody diversity is generated was largely settled in the 1970s by the discoveries of variable gene rearrangements and somatic hypermutation. This led to the paradigm that immunoglobulins are composed of two independent domains - variable and constant - that confer specificity and effector functions, respectively. However, since these early discoveries, there have been a series of observations of communication between the variable and constant domains that affects the overall antibody structure, which suggests that immunoglobulins have a more complex, interconnected functionality than previously thought. Another unresolved issue has been the genesis of 'restricted' antibody responses, characterized by the use of only a few variable region gene segments, despite the enormous potential combinatorial diversity. In this Perspective, we place recent findings related to immunoglobulin structure and function in the context of these immunologically important, historically unsolved problems to propose a new model for how antibody specificity is achieved without autoreactivity.
Post-translational protein modifications by the small ubiquitin-like modifier (SUMO) family have been shown to regulate immune cells in the context of infection, autoimmunity and, more recently, cancer. Recent clinical t...Post-translational protein modifications by the small ubiquitin-like modifier (SUMO) family have been shown to regulate immune cells in the context of infection, autoimmunity and, more recently, cancer. Recent clinical trials investigating sumoylation inhibition as a therapeutic approach for cancer have established that sumoylation has important immune modulatory effects. Sumoylation suppresses transcription factors in innate immune cells and in cytotoxic T cells through the direct modification of these factors, which leads to the recruitment of transcriptional repressor complexes containing histone deacetylases. By contrast, in regulatory T cells and T helper 17 cells, sumoylation of transcription factors can enhance transcriptional activity by recruiting transcriptional coactivators. Sumoylation is also involved in the repression of IFNB1 and endogenous retroviruses and is therefore important for regulating interferon expression. A central theme from literature is that the sumoylation of a group of proteins, instead of a single target, collectively contributes to the regulation of various immune processes. In this Review, we consider how these studies provide scientific basis for future exploration of SUMO-mediated immune modulation for the treatment of cancers and autoimmune disorders.
Personalized cell therapies for autoimmune diseases - such as autologous haematopoietic stem cell transplantation and chimeric antigen receptor-expressing T cells - have the potential to achieve sustained remission in pa...Personalized cell therapies for autoimmune diseases - such as autologous haematopoietic stem cell transplantation and chimeric antigen receptor-expressing T cells - have the potential to achieve sustained remission in patients with certain autoimmune diseases. The effective elimination of pathogenic lymphocytes and their subsequent repopulation with naive cells has been termed 'immune reset'. In this Perspective, we trace the origins of the immune reset concept and its clinical, cellular and molecular definitions, and we review current attempts to identify biomarkers for long-term clinical remission in autoimmune diseases. Emerging data from clinical trials support the concept that higher probabilities of long-term remission can be achieved with therapies that can more deeply and broadly deplete B cells than the anti-CD20 antibody rituximab. A better understanding of the cellular and molecular basis for immune reset and the biomarkers associated with this state should accelerate progress towards the goal of restoring a non-autoimmune state and sustaining remission, while reducing the need for chronic immunosuppression.
Elkayam E, Gervais FG, Wu H
… +2 more, Crackower MA, Lieberman J
Nat Rev Immunol
· 2025 Aug · PMID 40044809
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Recent studies indicate that the human lipopolysaccharide sensor caspase-4, unlike its mouse homologue caspase-11, is constitutively expressed and activates pro-IL-18 as well as gasdermin D-mediated pyroptosis. Activatio...Recent studies indicate that the human lipopolysaccharide sensor caspase-4, unlike its mouse homologue caspase-11, is constitutively expressed and activates pro-IL-18 as well as gasdermin D-mediated pyroptosis. Activation of human caspase-4 causes vascular leakage systemically and at the blood-brain barrier in mice and is implicated in the pathogenesis of a range of inflammatory diseases for which there are currently no effective therapies. These results suggest the therapeutic potential of modulating caspase-4 activity, and structural studies indicate that the caspase-4 exosite might be a promising inhibitory target.