Hussain T, Pereira M, Chisanga D
… +34 more, Dawson CA, Tang A, Thilakasiri P, Singh J, Ruppert M, Davey A, Man K, Murer P, Neil L, McGuinness C, Cao Y, Su CH, Nightingale R, Gdak K, Mason G, Grinsell D, Farrow H, Ngan N, Liong S, Wu J, McLucas S, Schedin P, Junnila A, Poutanen M, Haynes NM, Huntington ND, Chopin M, Gebhardt T, Pal B, Utzschneider DT, Mariadason JM, Kallies A, Britt KL, Vasanthakumar A
Women who have full-term pregnancies have a reduced risk of breast cancer, although the underlying mechanisms are not well understood. Here we show that tissue-resident memory-like T (T-like) cells are enriched in the br...Women who have full-term pregnancies have a reduced risk of breast cancer, although the underlying mechanisms are not well understood. Here we show that tissue-resident memory-like T (T-like) cells are enriched in the breasts of parous women and mice compared to nulliparous individuals. These cells develop during mid-gestation, persist after lactation and are closely associated with mammary epithelial cells, suggesting dependence on epithelial-derived signals. Impaired alveolar differentiation or a deficiency in epithelial cell-derived cytokines interleukin (IL)-15 and transforming growth factor (TGF)β diminished the expansion of mammary T-like cells. Single-cell transcriptomics revealed the expanded T-like cells were heterogeneous, comprising CD8αβ and CD8αα subsets. Lineage tracing showed that these T-like cells acquire effector functions and contribute to tumor control. Depletion of T-like cells abrogated breast tumor protection in parous mice, while enhanced IL-2Rβ signaling-induced T-like cells and conferred protection in nulliparous mice. Together, we show a mechanism by which pregnancy can induce anticipatory breast cancer protection in a tissue-specific manner.
Cell migration and strategic positioning within tissues is critical for the rapid mobilization of a T cell response. T cells must remain motile in both lymphoid and nonlymphoid tissues, which vary widely in mechanical pr...Cell migration and strategic positioning within tissues is critical for the rapid mobilization of a T cell response. T cells must remain motile in both lymphoid and nonlymphoid tissues, which vary widely in mechanical properties such as stiffness. Here we showed that activated T cells sensed mechanical cues and responded with changes in cell morphology, nuclear envelope composition and initiation of DNA repair to protect their genomic material from force-mediated damage. Increased mechanical input also drove the transcriptional reprogramming of activated T cells, including changes in many of the core genes shared by tissue-resident memory T cells across diverse tissues, by modulating the expression of the tissue-resident memory T cell-associated transcription factors Klf2, Runx3 and Hic1. Thus, mechanosensing by activated T cells impacted T cell fate, promoting a transcriptional program associated with tissue residency.
Paraskevopoulou V, Lin Z, Casado-Pelaez M
… +23 more, Grases D, Al-Santli W, Balandrán JC, Zhou F, Rashidfarrokhi A, Cross M, Yeung ST, Ntatsoulis K, Patel T, Chen X, Nicolet D, Escobosa M, Porta E, Trowbridge JJ, Khanna KM, Papagiannakopoulos T, Moreira AL, Kanagal-Shamanna R, Loghavi S, Tsirigos A, Eisfeld AK, Esteller M, Aifantis I
Acute myeloid leukemia (AML) is a blood cancer with poor survival outcomes. Acute respiratory failure frequently occurs due to leukemia infiltration of the lungs. Underlying mechanisms remain unexplored and therapeutic i...Acute myeloid leukemia (AML) is a blood cancer with poor survival outcomes. Acute respiratory failure frequently occurs due to leukemia infiltration of the lungs. Underlying mechanisms remain unexplored and therapeutic interventions remain empiric. Here we map the AML lung microenvironment at spatial and single-cell resolution. We show that extensive remodeling is coupled with inflammation and impaired tissue integrity and function. Steroid treatment significantly reduces AML burden and lung infiltration, improving oxygenation and pulmonary function. As a mechanistic correlate, the S-type lectin Lgals9 is triggered by inflammation and mediates cell-cell interactions within infiltrated lungs. Also, the alarmin IL-33 and its receptor (IL-1RL1) are involved in cell-cell interactions within the leukemic lung microenvironment. Targeting either the Lgals9 or IL-33 axis significantly decreases overall AML burden and lung infiltration through effects on both the immune microenvironment and AML cells. Our studies delineate pulmonary infiltration phenotypes in acute leukemia, enabling new treatment strategies.
The neuroimmune system, an extensive bidirectional communication system between neural cells and immune cells, utilizes evolutionarily conserved molecules, including cytokines, chemokines and trophic factors that partici...The neuroimmune system, an extensive bidirectional communication system between neural cells and immune cells, utilizes evolutionarily conserved molecules, including cytokines, chemokines and trophic factors that participate as mediators in both directions. While the initial discovery of classic immune molecules in the brain was interpreted as neuroinflammation, a broad literature demonstrates their essential roles in cognition during homeostatic brain function. These mechanisms include neural correlates of learning and memory, such as strengthening of neuronal networks and the generation of new neurons and synaptic connections. These processes take place throughout the brain, especially in the hippocampus, a major component of the brain of humans and other vertebrates that consolidates short-term memory into long-term memory and supports spatial navigation. This Review explores recent developments and understanding of immune molecules that orchestrate and participate in molecular mechanisms of memory formation. It also considers their potential efficacy as new targets to treat memory disorders.
Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition throug...Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.
Inflammatory memory enables cells to remember prior inflammatory signals, shaping their responses to subsequent challenges. While this phenomenon has been extensively characterized in immune cells and various tissues, re...Inflammatory memory enables cells to remember prior inflammatory signals, shaping their responses to subsequent challenges. While this phenomenon has been extensively characterized in immune cells and various tissues, recent reports suggest that both immune and nonimmune cells in the central nervous system (CNS) also exhibit inflammatory memory. In this Perspective, we synthesize emerging evidence of inflammatory memory in the CNS and discuss its underlying mechanisms. We highlight how epigenomic reprogramming through histone and DNA modifications, the recruitment of epigenetic regulators and nucleosome remodeling drive changes in gene expression kinetics central to inflammatory memory. We also examine mechanisms that maintain or reset inflammatory memory. By identifying shared principles and CNS-specific features, we propose conceptual frameworks to advance our understanding of CNS inflammatory memory and its implications for health and disease.
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central ne...Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression. Advances in genetic, neuropathological and experimental studies also underscore the potential role of the adaptive immune system in disease pathogenesis. Here we summarize the current understanding of how adaptive immunity can shape the progression of neurodegenerative diseases and highlight cross-disease parallels and potentially shared mechanisms. We also examine cellular events leading to the recruitment of peripheral immune cells to the CNS, as well as candidate antigens driving the adaptive immune response. Last, we discuss potential therapeutic strategies to treat neurodegeneration via the manipulation of adaptive immune cells.
Branchett WJ, Kim JW, Shields J
… +10 more, Chakravarty P, Lee J, Novsarka I, Slawinski H, Wilkinson KA, Wilkinson RJ, Kamil A, Verma R, Haldar P, O'Garra A
The local immune factors dictating whether individuals who have been infected with Mycobacterium tuberculosis remain healthy or progress to active tuberculosis (TB) have not been defined. Here we interrogated the airway...The local immune factors dictating whether individuals who have been infected with Mycobacterium tuberculosis remain healthy or progress to active tuberculosis (TB) have not been defined. Here we interrogated the airway immune response at single-cell resolution in bronchoalveolar lavage from positron emission and computed tomography-characterized recent TB household contacts, who either controlled the infection or progressed to TB disease, as well as of patients with active TB at diagnosis. Single-cell RNA sequencing revealed type I IFN-dependent and IFN-independent neutrophil signatures in bronchoalveolar lavage from patients with active TB and TB progressors. We report an inverse relationship between airway neutrophils and T cells, with T cells showing signatures of exhaustion, cytotoxicity and cell death in progressors and patients with active TB with a neutrophil-dominated airway profile. Conversely, we identified T cell signatures of protection in nonprogressor contacts dominated by genes related to regulation, quiescence and a stem-like profile. Our findings from early human airway responses in TB contacts reveal genes, pathways and cell states that may dictate infection outcome and inform strategies for developing effective host-directed therapies and vaccines.
Germinal centers (GCs) are a complex and important aspect of humoral immunity. How GCs deal with changing antigens remains unclear, yet this biology could be central to next-generation vaccine strategies such as germline...Germinal centers (GCs) are a complex and important aspect of humoral immunity. How GCs deal with changing antigens remains unclear, yet this biology could be central to next-generation vaccine strategies such as germline targeting. Here we demonstrate, in a mouse model with human immunodeficiency virus envelope surface protein immunogens, that rapid delivery of homologous or heterologous boosts results in highly positive outcomes. Rapid reimmunization expands on-target GC B cell (B) populations, which emerge almost exclusively from existing B cells. Early homologous boosting avoids prohibitive antibody titers and utilizes off-target antibodies to maximize the B response. Heterologous rapid boosting shifts affinity maturation towards the new antigen. The 'refueled' GCs are sustained, developing large affinity gains and evolving rapidly to bind wildtype HIV Env trimer within 56 days, even when using as few as two distinct antigens. These findings provide insights into GC biology and translatable paths to leveraging accelerated GC function.