Seminars in Immunopathology最新文献

CD4⁺ and CD8⁺ T lymphocytes mediate most of the adaptive immune response against tumors. Naïve T lymphocytes specific for tumor antigens are primed in lymph nodes by dendritic cells. Upon activation, antigen-specific T cells proliferate and differentiate into effector cells that migrate out of peripheral blood into tumor sites in an attempt to eliminate cancer cells. After accomplishing their function, most effector T cells die in the tissue, while a small fraction of antigen-specific T cells persist as long-lived memory cells, circulating between peripheral blood and lymphoid tissues, to generate enhanced immune responses when re-encountering the same antigen. A subset of memory T cells, called resident memory T (T_RM) cells, stably resides in non-lymphoid peripheral tissues and may provide rapid immunity independently of T cells recruited from blood. Being adapted to the tissue microenvironment, T_RM cells are potentially endowed with the best features to protect against the reemergence of cancer cells. However, when tumors give clinical manifestation, it means that tumor cells have evaded immune surveillance, including that of T_RM cells. Here, we review the current knowledge as to how T_RM cells are generated during an immune response and then maintained in non-lymphoid tissues. We then focus on what is known about the role of CD4⁺ and CD8⁺ T_RM cells in antitumor immunity and their possible contribution to the efficacy of immunotherapy. Finally, we highlight some open questions in the field and discuss how new technologies may help in addressing them.

Preterm infants are at particularly high risk for infectious diseases. As this vulnerability extends beyond the neonatal period into childhood and adolescence, preterm infants benefit greatly from infection-preventive measures such as immunizations. However, there is an ongoing discussion about vaccine safety and efficacy due to preterm infants' distinct immunological features. A significant proportion of infants remains un- or under-immunized when discharged from primary hospital stay. Educating health care professionals and parents, promoting maternal immunization and evaluating the potential of new vaccination tools are important means to reduce the overall burden from infectious diseases in preterm infants. In this narrative review, we summarize the current knowledge about vaccinations in premature infants. We discuss the specificities of early life immunity and memory function, including the role of polyreactive B cells, restricted B cell receptor diversity and heterologous immunity mediated by a cross-reactive T cell repertoire. Recently, mechanistic studies indicated that tissue-resident memory (Trm) cell populations including T cells, B cells and macrophages are already established in the fetus. Their role in human early life immunity, however, is not yet understood. Tissue-resident memory T cells, for example, are diminished in airway tissues in neonates as compared to older children or adults. Hence, the ability to make specific recall responses after secondary infectious stimulus is hampered, a phenomenon that is transcriptionally regulated by enhanced expression of T-bet. Furthermore, the microbiome establishment is a dominant factor to shape resident immunity at mucosal surfaces, but it is often disturbed in the context of preterm birth. The proposed function of Trm T cells to remember benign interactions with the microbiome might therefore be reduced which would contribute to an increased risk for sustained inflammation. An improved understanding of Trm interactions may determine novel targets of vaccination, e.g., modulation of T-bet responses and facilitate more individualized approaches to protect preterm babies in the future.

The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and recirculate through secondary lymphoid organs. Instead, subsets of immune cells continuously reside in tissues until being reactivated, e.g., by a recurring pathogen or other stimuli. Consequently, the concept of tissue-resident immunity has emerged, and substantial evidence is now available to support its pivotal function in maintaining tissue homeostasis, sensing challenges and providing antimicrobial protection. Surprisingly, insights on tissue-resident immunity in the barrier tissues of the female reproductive tract are sparse and only slowly emerging. The need for protection from vaginal and amniotic infections, the uniqueness of periodic tissue shedding and renewal of the endometrial barrier tissue, and the demand for a tailored decidual immune adaptation during pregnancy highlight that tissue-resident immunity may play a crucial role in distinct compartments of the female reproductive tract. This review accentuates the characteristics of tissue-resident immune cells in the vagina, endometrium, and the decidua during pregnancy and discusses their functional role in modulating the risk for infertility, pregnancy complications, infections, or cancer. We here also review data published to date on tissue-resident immunity in the male reproductive organs, which is still a largely uncharted territory.

The vasculature plays an essential role in the development and maintenance of blood-tissue interface homeostasis. Knowledge on the morphological and functional nature of the blood vessels in every single tissue is, however, very poor, but it is becoming clear that each organ is characterized by the presence of endothelial barriers with different properties fundamental for the maintenance of tissue resident immune homeostasis and for the recruitment of blood-trafficking immune cells. The tissue specificity of the vascular unit is dependent on the presence of differentiated endothelial cells that form continues, fenestrated, or sinusoidal vessels with different grades of permeability and different immune receptors, according to how that particular tissue needs to be protected. The gut-brain axis highlights the prominent role that the vasculature plays in allowing a direct and prompt exchange of molecules between the gut, across the gut vascular barrier (GVB), and the brain. Recently, we identified a new choroid plexus vascular barrier (PVB) which receives and integrates information coming from the gut and is fundamental in the modulation of the gut-brain axis. Several pathologies are linked to functional dysregulation of either the gut or the choroid plexus vascular barriers. In this review, we unveil the structural and functional analogies between the GVB and PVB, comparing their peculiar features and highlighting the functional role of pitcher and catcher of the gut-brain axis, including their role in the establishment of immune homeostasis and response upon systemic stimuli. We propose that when the gut vascular barrier-the main protecting system of the body from the external world-is compromised, the choroid plexus gatekeeper becomes a second barrier that protects the central nervous system from systemic inflammation.

The lung is a vital organ that incessantly faces external environmental challenges. Its homeostasis and unimpeded vital function are ensured by the respiratory epithelium working hand in hand with an intricate fine-tuned tissue-resident immune cell network. Lung tissue-resident immune cells span across the innate and adaptive immunity and protect from infectious agents but can also prove to be pathogenic if dysregulated. Here, we review the innate and adaptive immune cell subtypes comprising lung-resident immunity and discuss their ontogeny and role in distinct respiratory diseases. An improved understanding of the role of lung-resident immunity and how its function is dysregulated under pathological conditions can shed light on the pathogenesis of respiratory diseases.

A subset of memory T cells has been identified in the liver with a tissue-resident profile and the capacity for long-term 'lockdown'. Here we review how they are retained in, and adapted to, the hepatic microenvironment, including its unique anatomical features and metabolic challenges. We describe potential interactions with other local cell types and the need for a better understanding of this complex bidirectional crosstalk. Pathogen or tumour antigen-specific tissue-resident memory T cells (T_RM) can provide rapid frontline immune surveillance; we review the evidence for this in hepatotropic infections of major worldwide importance like hepatitis B and malaria and in liver cancers like hepatocellular carcinoma. Conversely, T_RM can be triggered by pro-inflammatory and metabolic signals to mediate bystander tissue damage, with an emerging role in a number of liver pathologies. We discuss the need for liver sampling to gain a window into these compartmentalised T cells, allowing more accurate disease monitoring and future locally targeted immunotherapies.

The identification of tissue-resident memory T cells (T_RM cells) has significantly improved our understanding of immunity. In the last decade, studies have demonstrated that T_RM cells are induced after an acute T-cell response, remain in peripheral organs for several years, and contribute to both an efficient host defense and autoimmune disease. T_RM cells are found in the kidneys of healthy individuals and patients with various kidney diseases. A better understanding of these cells and their therapeutic targeting might provide new treatment options for infections, autoimmune diseases, graft rejection, and cancer. In this review, we address the definition, phenotype, and developmental mechanisms of T_RM cells. Then, we further discuss the current understanding of T_RM cells in kidney diseases, such as infection, autoimmune disease, cancer, and graft rejection after transplantation.

The brain is an immune-privileged organ such that immune cell infiltration is highly regulated and better tolerating the introduction of antigen to reduce risk of harmful inflammation. Thus, the composition and the nature of the immune response is fundamentally different in the brain where avoiding immunopathology is prioritized compared to other peripheral organs. While the principle of immune privilege in the central nervous system (CNS) still holds true, the role of the immune system in the CNS has been revisited over the recent years. This redefining of immune privilege in the brain is a result of the recent re-discovery of the extensive CNS meningeal lymphatic system and the identification of resident T cells in the brain, meningeal layers, and its surrounding cerebrospinal fluid (CSF) in both humans and rodents. While neuro-immune interactions have been classically studied in the context of neuroinflammatory disease, recent works have also elucidated unconventional roles of immune-derived cytokines in neurological function, highlighting the many implications and potential of neuro-immune interactions. As a result, the study of neuro-immune interactions is becoming increasingly important in understanding both CNS homeostasis and disease. Here, we review the anatomically distinct immune compartments within the brain, the known mechanisms of leukocyte trafficking and infiltration into the CNS and unique transcriptional and functional characteristics of CNS-resident immune cells.

Parkinson's disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak's theory and model where pathological α-synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson's disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α-synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson's disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.