Recruitment Of Adaptive Immune Cells Research Articles

The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion.

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8+ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.

Scalable generation of functional human iPSC-derived CAR-macrophages that efficiently eradicate CD19-positive leukemia

BackgroundMacrophages have recently become attractive therapeutics in cancer immunotherapy. The potential of macrophages to infiltrate and influence solid malignancies makes them promising targets for the chimeric antigen receptor (CAR) technology...

Periprosthetic joint infection and immunity: Current understanding of host-microbe interplay.

Periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty. Even with current treatments, failure rates are unacceptably high with a 5-year mortality rate of 26%. Majority of the literature in the field has focused on development of better biomarkers for diagnostics and treatment strategies including innovate antibiotic delivery systems, antibiofilm agents, and bacteriophages. Nevertheless, the role of the immune system, our first line of defense during PJI, is not well understood. Evidence of infection in PJI patients is found within circulation, synovial fluid, and tissue and include numerous cytokines, metabolites, antimicrobial peptides, and soluble receptors that are part of the PJI diagnosis workup. Macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs)are initially recruited into the joint by chemokines and cytokines produced by immune cells and bacteria and are activated by pathogen-associated molecular patterns.While these cells are efficient killers of planktonic bacteria by phagocytosis, opsonization, degranulation, and recruitment of adaptive immune cells, biofilm-associated bacteria are troublesome. Biofilm is not only a physical barrier for the immune system but also elicits effector functions. Additionally, bacteria have developed mechanisms to evade the immune system by inactivating effector molecules, promoting killing or anti-inflammatory effector cell phenotypes, and intracellular persistence and dissemination. Understanding these shortcomings and the mechanisms by which bacteria can subvert the immune system may open new approaches to better prepare our own immune system to combat PJI. Furthermore, preoperative immune system assessment and screening for dysregulation may aid in developing preventative interventions to decrease PJI incidence.

Heterogeneity of type 2 innate lymphoid cells.

More than a decade ago, type 2 innate lymphoid cells (ILC2s) were discovered to be members of a family of innate immune cells consisting of five subsets that form a first line of defence against infections before the recruitment of adaptive immune cells. Initially, ILC2s were implicated in the early immune response to parasitic infections, but it is now clear that ILC2s are highly diverse and have crucial roles in the regulation of tissue homeostasis and repair. ILC2s can also regulate the functions of other type 2 immune cells, including T helper 2 cells, type 2 macrophages and eosinophils. Dysregulation of ILC2s contributes to type 2-mediated pathology in a wide variety of diseases, potentially making ILC2s attractive targets for therapeutic interventions. In this Review, we focus on the spectrum of ILC2 phenotypes that have been described across different tissues and disease states with an emphasis on human ILC2s. We discuss recent insights in ILC2 biology and suggest how this knowledge might be used for novel disease treatments and improved human health.

Deciphering the Labyrinthine System of the Immune Microenvironment in Recurrent Glioblastoma: Recent Original Advances and Lessons from Clinical Immunotherapeutic Approaches.

Simple SummaryActive communication between GBM cells and tumor-infiltrating immune components contributes to establishing an immunosuppressive environment where T cells are scarce and exhausted. This condition is particularly exacerbated upon recurrence, which is almost inevitable for GBM patients. Immunotherapeutic approaches, including checkpoint inhibitors, have demonstrated limited efficacy and failed to prolong survival or recurrent GBM patients. Nevertheless, many studies have shown that T cell priming is possible in the GBM microenvironment, and that T cell exhaustion or dysfunction can be reprogrammed. We will revisit data from the literature and report original results obtained from recurrent GBM patients treated with dendritic cells to demonstrate the role of the microenvironment in predicting immunotherapy response and influencing decisions for personalized therapies.The interpretation of the presence and function of immune infiltration in glioblastoma (GBM) is still debated. Over the years, GBM has been considered a cold tumor that is less infiltrated by effector cells and characterized by a high proportion of immunosuppressive innate immune cells, including GBM-associated microglia/macrophages (GAMs). In this context, the failure of checkpoint inhibitors, particularly in recurrent GBM (rGBM), caused us to look beyond the clinical results and consider the point of view of immune cells. The tumor microenvironment in rGBM can be particularly hostile, even when exposed to standard immunomodulatory therapies, and tumor-infiltrating lymphocytes (TILs), when present, are either dysfunctional or terminally exhausted. However, after checkpoint blockade therapy, it was possible to observe specific recruitment of adaptive immune cells and an efficient systemic immune response. In this review article, we attempt to address current knowledge regarding the tumor and immune microenvironment in rGBM. Furthermore, immunosuppression induced by GAMs and TIL dysfunction was revisited to account for genetic defects that can determine resistance to therapies and manipulate the immune microenvironment upon recurrence. Accordingly, we reevaluated the microenvironment of some of our rGBM patients treated with dendritic cell immunotherapy, with the goal of identifying predictive immune indicators of better treatment response.

Tumor-Derived PGE2 Gives NK Cells a Headache

Tumors use active immunosuppressive mechanisms to evade immune recognition and shape the local inflammatory environment. In this issue of Immunity, Bonavita etal. report that tumor-derived PGE2 blocks early activation of natural killer cells and interferes with subsequent adaptive immune cell recruitment to the tumor.

Lung T Cell Activation in an Outbred Pig Transplant and Ischemia-Reperfusion Injury Model

Purpose Primary graft dysfunction (PGD) contributes to morbidity and mortality after lung transplantation. Ischemia-reperfusion injury (IRI) is a major risk factor for PGD. While the adaptive immune system contributes to IRI, its role is not well understood. The pig lung transplant (LTx) IRI model is useful for pre-clinical testing: however, assessment of immune changes is limited by poor pig-specific reagents. Our objective was to establish strategies for studying changes in adaptive immune cell recruitment and activation in a pig IRI model. Methods Pig lung tissue samples (standardized for size) were collected from separate 4h and 72h pig IRI survival models. Samples included: donor lung post-flush but prior to cold ischemic preservation (pre-CI), donor lung post-CI prior to transplant, post-transplant left allograft with IRI (IRI), and contralateral right native lung (no IRI). Novel porcine flow cytometry panels were developed and used to characterize T lung leukocytes. A one-way ANOVA was used; p Results Both T cell and non-T cell lung tissue leukocytes trended down during CI (post-CI vs. pre-CI) (Fig A, B). After reperfusion, non-T cell leukocytes generally increased (Fig B) without a marked change in CD3 T cells (4h IRI vs. post-CI) (Fig A). The CD4:CD8 ratio increased compared to post-CI in both the allograft and native lung but returned to a CD8 predominant ratio at 72h post-IRI (Fig C). The effector:non-effector T cell ratio increased 4h post-IRI and remained high at 72h post-IRI (Fig D). Concurrently, IRI was linked with a significant decrease in naive CD4 T cells, which were almost undetectable at 72h post-IRI (Fig E). Conclusion In a pig LTx IRI model, substantial T cell activation was seen, supporting the involvement of the adaptive immunity in lung IRI, despite minimal T cell recruitment. The flow cytometric strategies developed will be used to further define adaptive immune responses in pig IRI, effects of IRI-directed therapies, and their role in the development of PGD.

Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.

Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

Enhanced Th1/Th17 Functions of CD161+ CD8+ T Cells in Mucosal Tissues of Rhesus Macaques.

Expression of the C-type lectin-like receptor CD161 by human T cells is associated with type-17 responses, which play critical regulatory roles in immunity and inflammation at mucosal sites. However, the functions of CD161-expressing T cells in macaques, the pre-clinical model of several human diseases, remain unknown. This study examined the phenotypic and functional characteristics of CD161+ T cells in peripheral blood, mucosal tissues and lymph nodes of rhesus macaques. Majority of CD161-expressing T cells in peripheral blood and lung/intestinal mucosal tissues of rhesus macaques were found to be CD8+CD4– in phenotype. There was a significant enrichment of CD161+CD8+ T cells in the lungs and colonic mucosa (16.1%±6.6 and 16.8%±5.7) in comparison to peripheral blood (4.2%±1.2) and mesenteric lymph nodes (1.3%±0.8). Regardless of the tissue compartment, CD161+CD8+ T cells mainly comprised of γδ T cells and TCR Vα7.2+ MAIT cells (up to 80%), and displayed Th1 and Th17 cytokine responses to mitogen stimulation. Mucosal CD161+CD8+ T cells were characterized by very high expression of CD69, a recent activation marker that is preferentially expressed on tissue resident cells. Furthermore, lung and colonic mucosal CD161+CD8+ T cells showed enhanced IFN-γ, IL-17, and Perforin production in comparison to those in blood. Thus, macaque CD161+CD8+ T cells represent mucosal tissue-homing innate-like CD8+ T-cell populations with Th1/Th17 type cytokine and cytotoxic effector functions that can potentially enhance the recruitment of adaptive immune cells and control initial pathogen burden/dissemination in tissues. Analysis of their role in early immune responses to mucosal pathogens will be valuable in the design of vaccines and therapeutics.

Abstract 668: The Role of IL-27 Receptor Signaling in the Development of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a cardiovascular disease, which is characterized by aortic wall dilation with subsequent rupture and internal bleeding. Inflammatory reactions in the vessel wall are likely essential for AAA pathogenesis, just like they are important for the development of another vascular pathology- atherosclerosis, which can predispose to AAA formation in a context-dependent manner. While inflammatory cytokines were shown to promote atherosclerosis and AAA, little is known about contribution of anti-inflammatory cytokines with regard to their ability to control vascular inflammation. Interleukin (IL)-27 signaling is required to suppress atherosclerosis development but its function in AAA remains unknown. We utilize Angiotensin II (AngII) model to evaluate the role of IL-27R signaling in pathogenesis of AAA. AngII containing pumps were surgically implanted into Il27ra-/- x Ldlr-/-; Il27ra -/- x Apoe-/- and Il27ra+/- littermate controls and AAA progression was analyzed 4 weeks later. Surprisingly, we found attenuated AAA progression in Il27ra-/- mice compared to Il27ra+/- and wt counterparts. The latter developed large AAA with visual hemorrhage into the artery wall, while Il27ra-/- mice developed small AAA with fewer myeloid cells and T cells. Moreover, opposite to aortic arches, T cells in abdominal aortas of Il27ra-/- mice produced less inflammatory IL-17A, while IFNγ production was unchanged. Interestingly, we found enhanced production of “Th2-like” cytokines IL-4 and IL-13, by NK cells and Type 2 Innate lymphoid cells (ILC2) in Il27ra deficient mice, which correlated with the protection from AAA. Overall, we conclude that immunoregulatory cytokine IL-27 can differentially control atherosclerosis and AAA development by regulating innate and adaptive immune cell recruitment and cytokine production in the aortic wall.

Lung Irradiation Increases Mortality After Influenza A Virus Challenge Occurring Late After Exposure

To address whether irradiation-induced changes in the lung environment alter responses to a viral challenge delivered late after exposure but before the appearance of late lung radiation injury. C57BL/6J mice received either lung alone or combined lung and whole-body irradiation (0-15 Gy). At 10 weeks after irradiation, animals were infected with 120 HAU influenza virus strain A/HKx31. Innate and adaptive immune cell recruitment was determined using flow cytometry. Cytokine and chemokine production and protein leakage into the lung after infection were assessed. Prior irradiation led to a dose-dependent failure to regain body weight after infection and exacerbated mortality, but it did not affect virus-specific immune responses or virus clearance. Surviving irradiated animals displayed a persistent increase in total protein in bronchoalveolar lavage fluid and edema. Lung irradiation increased susceptibility to death after infection with influenza virus and impaired the ability to complete recovery. This altered response does not seem to be due to a radiation effect on the immune response, but it may possibly be an effect on epithelial repair.

Differential effects of interleukin-17 receptor signaling on innate and adaptive immunity during central nervous system bacterial infection

Although IL-17A (commonly referred to as IL-17) has been implicated in the pathogenesis of central nervous system (CNS) autoimmune disease, its role during CNS bacterial infections remains unclear. To evaluate the broader impact of IL-17 family members in the context of CNS infection, we utilized IL-17 receptor (IL-17R) knockout (KO) mice that lack the ability to respond to IL-17, IL-17F and IL-17E (IL-25). In this article, we demonstrate that IL-17R signaling regulates bacterial clearance as well as natural killer T (NKT) cell and gamma-delta (γδ) T cell infiltrates during Staphylococcus aureus-induced brain abscess formation. Specifically, when compared with wild-type (WT) animals, IL-17R KO mice exhibited elevated bacterial burdens at days 7 and 14 following S. aureus infection. Additionally, IL-17R KO animals displayed elevated neutrophil chemokine production, revealing the ability to compensate for the lack of IL-17R activity. Despite these differences, innate immune cell recruitment into brain abscesses was similar in IL-17R KO and WT mice, whereas IL-17R signaling exerted a greater influence on adaptive immune cell recruitment. In particular, γδ T cell influx was increased in IL-17R KO mice at day 7 post-infection. In addition, NK1.1high infiltrates were absent in brain abscesses of IL-17R KO animals and, surprisingly, were rarely detected in the livers of uninfected IL-17R KO mice. Although IL-17 is a key regulator of neutrophils in other infection models, our data implicate an important role for IL-17R signaling in regulating adaptive immunity during CNS bacterial infection.

Innate Immune Activation in Primary HIV‐1 Infection

There is growing evidence that highlights the role of the immune response during acute human immunodeficiency virus type 1 (HIV-1) infection in the control or development of disease. The adaptive immune responses do not appear until after HIV-1 infection is already well established, so the role of earlier and faster-responding innate immunity needs to be more closely scrutinized. In particular, 2 aspects of innate immunity for which there are growing research developments will be examined in this review: the actions of type I interferons and natural killer cells. These two components of the innate immune response contribute to viral control both by killing infected cells and by modulating other immune cells that develop. However, the role of interferon α in immune activation is a double-edged sword, causing recruitment of adaptive immune cells that can assist in viral control but concurrently contributing to immune activation-dependent disease progression. Understanding the complexity of how innate responses affect the outcome of HIV-1 infection will help in the development of vaccines that can use innate immunity to enhance viral control with minimal pathogenesis.

Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice

Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS. Pulmonary leptin expression was analyzed by immunohistochemistry and real-time PCR. Pulmonary inflammation upon 4 wk CS exposure was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue of WT, ob/ob, and db/db mice. Immunohistochemical analysis revealed leptin expression in bronchial epithelial cells, pneumocytes, alveolar macrophages, and bronchial/vascular smooth muscle cells. The 4 and 24 wk CS exposure increased leptin expression in bronchial epithelial cells and pneumocytes versus air-exposed WT mice (p<0.05). The 4 wk CS exposure resulted in increased accumulation of neutrophils, dendritic cells, macrophages, and lymphocytes in BALF and lung tissue of WT, ob/ob, and db/db mice. CS-exposed ob/ob and db/db mice showed in general higher numbers of neutrophils and lower numbers of CD4+, CD8+, and dendritic cells versus CS-exposed WT mice. Consistently, CXCL1 levels were enhanced in BALF of CS-exposed ob/ob and db/db mice versus WT mice (p<0.05). Exogenous leptin administration completely restored the skewed inflammatory profile in ob/ob mice. These data reveal an important role of leptin in modulating innate and adaptive immunity after CS inhalation in mice.