Antiretroviral therapy (ART) has markedly improved the life-expectancy of people living with HIV. However, during both HIV infection of humans and simian immunodeficiency virus infection of macaques, virus replication al...Antiretroviral therapy (ART) has markedly improved the life-expectancy of people living with HIV. However, during both HIV infection of humans and simian immunodeficiency virus infection of macaques, virus replication almost invariably rebounds upon ART interruption, due to the long-term persistency of a pool of latently infected cells harbouring integrated, replication-competent virus (known as the virus reservoir). Solving this 'HIV reservoir problem' is the key to achieving a cure (or at least a persistent remission) for HIV infection. Here, we summarize the key scientific evidence supporting the hypothesis that host immune responses, including those mediated by CD8 T cells, B cells, antibodies and innate immune cells, affect the size, clonality, and cellular, tissue and organ distribution of the HIV reservoir. Importantly, we believe that any solution to the 'reservoir problem' must address not only the multifaceted interactions between HIV and the host immune system, but also the complex interplay between the immunobiology of memory CD4 T helper cells (which form the main virus reservoir) and the molecular mechanisms that regulate HIV latency and reactivation. These concepts provide the rationale to develop new, immune-based approaches to 'cure' HIV infection; we review recent efforts to develop such therapies and their efficacy (or lack thereof) in disrupting the establishment and/or persistence of the virus reservoir in preclinical animal models and human clinical trials.
B cells have long been understood to be drivers of both humoral and cellular immunity. Recent advances underscore this importance but also indicate that in infection, inflammatory disease and cancer, B cells function dir...B cells have long been understood to be drivers of both humoral and cellular immunity. Recent advances underscore this importance but also indicate that in infection, inflammatory disease and cancer, B cells function directly at sites of inflammation and form tissue-resident memory populations. The spatial organization and cellular niches of tissue B cells have profound effects on their function and on disease outcome, as well as on patient response to therapy. Here we review the role of B cells in peripheral tissues in homeostasis and disease, and discuss the newly identified cellular and molecular signals that are involved in regulating their activity. We integrate emerging data from multi-omic human studies with experimental models to propose a framework for B cell function in tissue inflammation and homeostasis.
Nat Rev Immunol
· 2025 Jul · PMID 39891000
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A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has bro...A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.
The peripheral immune system communicates with the brain through complex anatomical routes involving the skull, the brain borders, circumventricular organs and peripheral nerves. These immune-brain communication pathways...The peripheral immune system communicates with the brain through complex anatomical routes involving the skull, the brain borders, circumventricular organs and peripheral nerves. These immune-brain communication pathways were classically considered to be dormant under physiological conditions and active only in cases of infection or damage. Yet, peripheral immune cells and signals are key in brain development, function and maintenance. In this Perspective, we propose an alternative framework for understanding the mechanisms of immune-brain communication. During brain development and in homeostasis, these anatomical structures allow selected elements of the peripheral immune system to affect the brain directly or indirectly, within physiological limits. By contrast, in ageing and pathological settings, detrimental peripheral immune signals hijack the existing communication routes or alter their structure. We discuss why a diversity of communication channels is needed and how they work in relation to one another to maintain homeostasis of the brain.
Kidney diseases are widespread and represent a considerable medical, social and economic burden. However, there has been marked progress in understanding the immunological aspects of kidney disease. This includes the ide...Kidney diseases are widespread and represent a considerable medical, social and economic burden. However, there has been marked progress in understanding the immunological aspects of kidney disease. This includes the identification of distinct intrarenal immunological niches and characterization of kidney disease endotypes according to the underlying molecular immunopathology, as well as a better understanding of the pathological roles for T cells, mononuclear phagocytes and B cells and the renal elements they target. These insights have improved the diagnosis of kidney disease. Here, we discuss new developments in our understanding of kidney immunology, focusing on immune mechanisms of disease and their translational implications for the diagnosis and treatment of kidney disease. We also describe the immune-mediated crosstalk between the kidney and other organs that influences kidney disease and extrarenal inflammation.