Stem cells maintain tissue architecture by replacing differentiated cells at steady state and upon injury. Implementing this cornerstone role requires protection of stem cells from pathogens and from the toxic effects of...Stem cells maintain tissue architecture by replacing differentiated cells at steady state and upon injury. Implementing this cornerstone role requires protection of stem cells from pathogens and from the toxic effects of immune system activation. However, the pro-inflammatory innate immune mechanisms that protect differentiated cells from infection are poorly functional in stem cells. Instead, stem cells employ other specific defence mechanisms, such as antiviral RNA interference. At steady state, the proliferation and differentiation of tissue stem cells is regulated by multiple cell types, including immune cells. Following sterile tissue injury or during infection, the immune response - in addition to controlling pathogens and clearing cell debris - orchestrates tissue repair by fine-tuning stem cell activity, through direct cell-cell contacts and via inflammatory mediators such as cytokines. There is thus stem-immune cross-talk that is fundamental to the maintenance of tissue homeostasis. Inflammageing, which is defined as the age-driven elevation of inflammation and is associated with an altered immune cell composition, profoundly affects this stem-immune cross-talk, impacting the ability to repair tissues and participating in ageing of the whole organism.
Uterine inflammation encompasses several conditions, including endometritis, which is a local innate immune response, usually to bacteria. Endometritis is an important veterinary and medical problem that can result in in...Uterine inflammation encompasses several conditions, including endometritis, which is a local innate immune response, usually to bacteria. Endometritis is an important veterinary and medical problem that can result in infertility and/or recurrent pregnancy loss. This Review aims to summarize animal models that can be used to uncover the immune pathways responsible for uterine inflammation and their value for screening novel, putative therapies. We discuss large animal models of endometritis, particularly the well-used bovine system and the value that may be added by further developing porcine systems. Animal cells and tissue explants can be ethically sourced, and these models can replace or reduce the need for live animal studies and overcome the practical issues of harvesting endometrial material from women. We explain how these models of endometritis show great potential for advancing our understanding of the immune dysfunction underlying susceptibility to the condition, and for early-stage drug discovery.
Connections between the nervous and immune systems are increasingly recognized as central to brain-body physiology. In this Review, we examine how these systems collaborate to detect and respond to both internal and exte...Connections between the nervous and immune systems are increasingly recognized as central to brain-body physiology. In this Review, we examine how these systems collaborate to detect and respond to both internal and external stimuli - such as psychological stress, circadian cues, infection, and tissue injury. Rather than operating in isolation, the nervous and immune systems form an integrated network that is more than the sum of its parts. They share a common architecture and vocabulary, enabling bidirectional connection and communication that modulate immune cell characteristics throughout the body. We review immune-nervous interactions within two complementary frameworks: first, a spatial framework that distinguishes communication in the brain, communication within peripheral organs, and communication across distance; and second, a temporal framework that maps nervous system influence across the operational lifespan of the immune system - specifically focusing on how the nervous system impacts immune cell development, distribution, and execution of functions. Finally, we highlight key tools, clinical applications, and questions for future research on how both systems coordinate to respond to somatic and environmental stressors.
The formation of new blood vessels - known as angiogenesis - is essential for the growth and spread of solid tumours. It is promoted by the hypoxic conditions that develop in growing tumours and drive the expression of p...The formation of new blood vessels - known as angiogenesis - is essential for the growth and spread of solid tumours. It is promoted by the hypoxic conditions that develop in growing tumours and drive the expression of pro-angiogenic growth factors by tumour cells and various stromal cells. However, the tumour-associated vasculature (TAV) generated by angiogenesis is abnormal and is a key barrier to T cell entry into tumours. Moreover, the TAV creates a hostile microenvironment owing to an accumulation of suppressive immune cells, hypoxic and acidic conditions, and high interstitial pressure, which all limit the function and survival of effector T cells. Here, we present the mechanisms of T cell migration into tumours, including via high endothelial venules, and the importance of tertiary lymphoid structures, which function as privileged sites for antigen presentation, activation and co-stimulation of T cells, for mounting effective antitumour immunity. We describe how the tumour vasculature limits antitumour T cell responses and how T cell responses could be improved by therapeutic targeting of the TAV. In particular, the use of combination therapies that aim to normalize tumour blood vessels, favourably reprogramme endogenous immunity, and support T cell trafficking, function and persistence will be key to improving clinical responses.
Nat Rev Immunol
· 2025 Nov · PMID 40571771
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Food allergy is an acute IgE-mediated reaction that occurs in response to food components and affects 1-10% of the global population. It is often thought to be a disease of the gastrointestinal tract, in which oral expos...Food allergy is an acute IgE-mediated reaction that occurs in response to food components and affects 1-10% of the global population. It is often thought to be a disease of the gastrointestinal tract, in which oral exposure to a food allergen induces an IgE-sensitizing response that primes the host immune system to react to the eliciting allergen following subsequent oral exposure. However, emerging evidence from clinical and basic research studies suggests that maladaptive immune responses in the skin also contribute to the development of food allergy. These responses can promote the development of food-specific IgE and reshape the gut immune microenvironment in a manner that predisposes to IgE-mediated activation of mast cells and clinical manifestations of allergic disease following subsequent food exposures. In this Review, we discuss how different routes of exposure to food antigens can contribute to allergic sensitization and describe how mast cells ultimately drive the allergic reaction to these food allergens.
During pregnancy, the maternal immune system must navigate a balance between fetal tolerance and a response to acquired microbial infections. Cells at the maternal-fetal interface coordinate this response throughout gest...During pregnancy, the maternal immune system must navigate a balance between fetal tolerance and a response to acquired microbial infections. Cells at the maternal-fetal interface coordinate this response throughout gestational stages in a dynamic manner, integrating endocrine, developmental, inflammatory and metabolic cues. Although many maternal and fetal cell types activate innate immune signalling pathways in response to infections, excessive inflammation can disrupt tolerance, affect placental function and impair fetal development, leading to congenital disease and other pregnancy complications. In this Review, we discuss the mechanisms of pathogen recognition in the maternal and fetal compartments of the placenta and the consequences of these responses to pregnancy outcomes.
Iron is a cofactor for hundreds of enzymes and biochemical processes that support cellular metabolism across the kingdoms of life. Because of this, the host and pathogen compete for iron as a vital resource. Moreover, re...Iron is a cofactor for hundreds of enzymes and biochemical processes that support cellular metabolism across the kingdoms of life. Because of this, the host and pathogen compete for iron as a vital resource. Moreover, research has shown that iron acquisition and iron trafficking have substantial effects on the immune system. This is especially important because iron-related disorders - both deficiency and overload - are common worldwide. In this Review, we describe how immune cells acquire and use iron, which branches of the immune system are most affected by iron and how changes in iron availability can affect infectious diseases, autoinflammatory disorders and antitumour immunity. We also discuss key unanswered questions and potential therapeutic opportunities to manipulate immunity by controlling iron trafficking.
Lefrançais E, Hudrisier D, Neyrolles O
… +2 more, Behar SM, Ernst JD
Nat Rev Immunol
· 2025 Nov · PMID 40514544
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Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), results in more human mortality than any other single pathogen, in part because of the lack of an effective vaccine. Although T cells are essential...Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), results in more human mortality than any other single pathogen, in part because of the lack of an effective vaccine. Although T cells are essential for immunity to TB, the mechanisms that provide protective immunity are poorly understood. In this Review, we describe current gaps in our knowledge about T cell-mediated immune responses to M. tuberculosis and discuss how recent technologies, including multiphoton intravital microscopy, spatial multiomics and high-resolution in vivo analyses of cell-cell interactions, may be used to gain insights that can inform the design of T cell-targeted TB vaccines.
Microglia, the resident immune cells of the brain, are now recognized as being active participants in the onset and progression of many neurological and neuropsychiatric disorders. As a result, substantial effort has bee...Microglia, the resident immune cells of the brain, are now recognized as being active participants in the onset and progression of many neurological and neuropsychiatric disorders. As a result, substantial effort has been made in finding ways to target, deplete or modulate the aberrant phenotypes of the microglia that are present in these different disease states, albeit with varied levels of success. The gut microbiota has recently emerged as a master regulator of microglia throughout the lifespan; here, we propose that this microbiota-microglia cross-talk may have major implications for our understanding of neurological disorders and neuropsychiatric diseases. We focus on the latest advances in understanding gut-microglia communication in the context of microglial heterogeneity and microglia-related functions, as well as considering the evidence for effects of these pathways on diseases and disorders of the central nervous system. We also address the challenges, opportunities and clinical implications of this emerging area of research.