γδ T cell migration: Separating trafficking from surveillance behaviors at barrier surfaces.
Immunological reviews
γδ T cells are found in highest numbers at barrier surfaces throughout the body, including the skin, intestine, lung, gingiva, and uterus. Under homeostatic conditions, γδ T cells provide immune surveillance of the epidermis, intestinal, and oral mucosa, whereas the presence of pathogenic microorganisms in the dermis or lungs elicits a robust γδ17 response to clear the infection. Although T cell migration is most frequently defined in the context of trafficking, analysis of specific migratory behaviors of lymphocytes within the tissue microenvironment can provide valuable insight into their function. Intravital imaging and computational analyses have been used to define "search" behavior associated with conventional αβ T cells; however, based on the known role of γδ T cells as immune sentinels at barrier surfaces and their TCR-independent functions, we put forth the need to classify distinct migratory patterns that reflect the surveillance capacity of these unconventional lymphocytes. This review will focus on how γδ T cells traffic to various barrier surfaces and how recent investigation into their migratory behavior has provided unique insight into the contribution of γδ T cells to barrier immunity.
10.1111/imr.12915
Shaped by the epithelium - postnatal immune mechanisms of oral homeostasis.
Zubeidat Khaled,Hovav Avi-Hai
Trends in immunology
The first encounter of mucosal barriers with the microbiota initiates host-microbiota feedback loops instructing the tailored development of both the immune system and microbiota at each mucosal site. Once established, balanced immunological interactions enable symbiotic relationships with the microbiota in adult life. This process has been extensively investigated in the mammalian monolayer epithelium-covered intestine and lung mucosae; however, the postnatal mechanisms engaged by the oral mucosa to establish homeostasis are currently being discovered. Here, we discuss the early life dialogue between the oral mucosa and the microbiota, with particular emphasis on the central role the multilayer epithelium plays to protect the oral mucosa. These intricate and unique postnatal immunological processes shape oral homeostasis, which can potentially affect buccal and systemic health in adult life.
10.1016/j.it.2021.05.006
Depleting CD103+ resident memory T cells in vivo reveals immunostimulatory functions in oral mucosa.
The Journal of experimental medicine
The oral mucosa is a frontline for microbial exposure and juxtaposes several unique tissues and mechanical structures. Based on parabiotic surgery of mice receiving systemic viral infections or co-housing with microbially diverse pet shop mice, we report that the oral mucosa harbors CD8+ CD103+ resident memory T cells (TRM), which locally survey tissues without recirculating. Oral antigen re-encounter during the effector phase of immune responses potentiated TRM establishment within tongue, gums, palate, and cheek. Upon reactivation, oral TRM triggered changes in somatosensory and innate immune gene expression. We developed in vivo methods for depleting CD103+ TRM while sparing CD103neg TRM and recirculating cells. This revealed that CD103+ TRM were responsible for inducing local gene expression changes. Oral TRM putatively protected against local viral infection. This study provides methods for generating, assessing, and in vivo depleting oral TRM, documents their distribution throughout the oral mucosa, and provides evidence that TRM confer protection and trigger responses in oral physiology and innate immunity.
10.1084/jem.20221853
CD8 tissue-resident memory T cells induce oral lichen planus erosion via cytokine network.
eLife
CD8 tissue-resident memory T (CD8 Trm) cells play key roles in many immune-inflammation-related diseases. However, their characteristics in the pathological process of oral lichen planus (OLP) remains unclear. Therefore, we investigated the function of CD8 Trm cells in the process of OLP. By using single-cell RNA sequencing profiling and spatial transcriptomics, we revealed that CD8 Trm cells were predominantly located in the lamina propria adjacent to the basement membrane and were significantly increased in patients with erosive oral lichen planus (EOLP) compared to those with non-erosive oral lichen planus (NEOLP). Furthermore, these cells displayed enhanced cytokine production, including IFN-γ (Interferon-gamma, a pro-inflammatory signaling molecule), TNF-α (Tumor Necrosis Factor-alpha, a cytokine regulating inflammation), and IL-17 (Interleukin-17, a cytokine involved in immune response modulation), in patients with EOLP. And our clinical cohort of 1-year follow-up was also supported the above results in RNA level and protein level. In conclusion, our study provided a novel molecular mechanism for triggering OLP erosion by CD8 Trm cells to secrete multiple cytokines, and new insight into the pathological development of OLP.
10.7554/eLife.83981
Distinct fibroblast progenitor subpopulation expedites regenerative mucosal healing by immunomodulation.
The Journal of experimental medicine
Injuries that heal by fibrosis can compromise organ function and increase patient morbidity. The oral mucosal barrier has a high regenerative capacity with minimal scarring, but the cellular mechanisms remain elusive. Here, we identify distinct postnatal paired-related homeobox-1+ (Prx1+) cells as a critical fibroblast subpopulation that expedites mucosal healing by facilitating early immune response. Using transplantation and genetic ablation model in mice, we show that oral mucosa enriched with Prx1+ cells heals faster than those that lack Prx1+ cells. Lineage tracing and scRNA-seq reveal that Prx1+ fibroblasts exhibit progenitor signatures in physiologic and injured conditions. Mechanistically, Prx1+ progenitors accelerate wound healing by differentiating into immunomodulatory SCA1+ fibroblasts, which prime macrophage recruitment through CCL2 as a key part of pro-wound healing response. Furthermore, human Prx1+ fibroblasts share similar gene and spatial profiles compared to their murine counterpart. Thus, our data suggest that Prx1+ fibroblasts may provide a valuable source in regenerative procedures for the treatment of corneal wounds and enteropathic fibrosis.
10.1084/jem.20221350
Epithelial-derived interleukin-23 promotes oral mucosal immunopathology.
Immunity
At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.
10.1016/j.immuni.2024.02.020
Tissue-Specific Immunity at the Oral Mucosal Barrier.
Moutsopoulos Niki M,Konkel Joanne E
Trends in immunology
The oral mucosal barrier is constantly exposed to a plethora of triggers requiring immune control, including a diverse commensal microbiome, ongoing damage from mastication, and dietary and airborne antigens. However, how these tissue-specific cues participate in the training of immune responsiveness at this site is minimally understood. Moreover, the mechanisms mediating homeostatic immunity at this interface are not yet fully defined. Here we present basic aspects of the oral mucosal barrier and discuss local cues that may modulate and train local immune responsiveness. We particularly focus on the immune cell network mediating immune surveillance at a specific oral barrier, the gingiva - a constantly stimulated and dynamic environment where homeostasis is often disrupted, resulting in the common inflammatory disease periodontitis.
10.1016/j.it.2017.08.005
Transcriptional signature primes human oral mucosa for rapid wound healing.
Science translational medicine
Oral mucosal wound healing has long been regarded as an ideal system of wound resolution. However, the intrinsic characteristics that mediate optimal healing at mucosal surfaces are poorly understood, particularly in humans. We present a unique comparative analysis between human oral and cutaneous wound healing using paired and sequential biopsies during the repair process. Using molecular profiling, we determined that wound-activated transcriptional networks are present at basal state in the oral mucosa, priming the epithelium for wound repair. We show that oral mucosal wound-related networks control epithelial cell differentiation and regulate inflammatory responses, highlighting fundamental global mechanisms of repair and inflammatory responses in humans. The paired comparative analysis allowed for the identification of differentially expressed SOX2 (sex-determining region Y-box 2) and PITX1 (paired-like homeodomain 1) transcriptional regulators in oral versus skin keratinocytes, conferring a unique identity to oral keratinocytes. We show that SOX2 and PITX1 transcriptional function has the potential to reprogram skin keratinocytes to increase cell migration and improve wound resolution in vivo. Our data provide insights into therapeutic targeting of chronic and nonhealing wounds based on greater understanding of the biology of healing in human mucosal and cutaneous environments.
10.1126/scitranslmed.aap8798
Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier.
Science (New York, N.Y.)
Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota trigger extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the αβ integrin receptor and activates effector functions, including the production of reactive oxygen species and neutrophil extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis in mice and humans. Concordantly, genetic polymorphisms in , encoding plasminogen, are associated with common forms of periodontal disease. Thus, fibrin is a critical regulator of neutrophil effector function, and fibrin-neutrophil engagement may be a pathogenic instigator for a prevalent mucosal disease.
10.1126/science.abl5450
An Overview of Physical, Microbiological and Immune Barriers of Oral Mucosa.
Şenel Sevda
International journal of molecular sciences
The oral mucosa, which is the lining tissue of the oral cavity, is a gateway to the body and it offers first-line protection against potential pathogens, exogenous chemicals, airborne allergens, etc. by means of its physical and microbiological-immune barrier functions. For this reason, oral mucosa is considered as a mirror to the health of the individual as well as a guard or early warning system. It is organized in two main components: a physical barrier, which consists of stratified epithelial cells and cell-cell junctions, and a microbiological-immune barrier that keeps the internal environment in a condition of homeostasis. Different factors, including microorganism, saliva, proteins and immune components, have been considered to play a critical role in disruption of oral epithelial barrier. Altered mucosal structure and barrier functions results in oral pathologies as well as systemic diseases. About 700 kinds of microorganisms exist in the human mouth, constituting the oral microbiota, which plays a significant role on the induction, training and function of the host immune system. The immune system maintains the symbiotic relationship of the host with this microbiota. Crosstalk between the oral microbiota and immune system includes various interactions in homeostasis and disease. In this review, after reviewing briefly the physical barriers of oral mucosa, the fundamentals of oral microbiome and oral mucosal immunity in regard to their barrier properties will be addressed. Furthermore, their importance in development of new diagnostic, prophylactic and therapeutic strategies for certain diseases as well as in the application for personalized medicine will be discussed.
10.3390/ijms22157821
The Bigger Picture: Why Oral Mucosa Heals Better Than Skin.
Waasdorp Maaike,Krom Bastiaan P,Bikker Floris J,van Zuijlen Paul P M,Niessen Frank B,Gibbs Susan
Biomolecules
Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, which generally heals faster compared to skin. Several studies have identified differences between oral and skin wound healing. Most of these studies however focus only on a single stage of wound healing or a single cell type. The aim of this review is to provide an extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic properties of resident cells and differential expression of cytokines and growth factors, multiple external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased extracellular matrix remodeling all contribute to the superior wound healing and reduced scar formation in oral mucosa, compared to skin.
10.3390/biom11081165
Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity.
Science immunology
The oral mucosa is a primary barrier site and a portal for entry of microbes, food, and airborne particles into the gastrointestinal tract. Nonetheless, mucosal immunity at this barrier remains understudied compared with other anatomical barrier sites. Here, we review basic aspects of oral mucosal histology, the oral microbiome, and common and clinically significant diseases that present at oral mucosal barriers. We particularly focus on the role of interleukin-17 (IL-17)/T helper 17 (T17) responses in protective immunity and inflammation in the oral mucosa. IL-17/T17 responses are highly relevant to maintaining barrier integrity and preventing pathogenic infections by the oral commensal fungus On the other hand, aberrant IL-17/T17 responses are implicated in driving the pathogenesis of periodontitis and consequent bone and tooth loss. We discuss distinct IL-17-secreting T cell subsets, emphasizing their regulation and function in oropharyngeal candidiasis and periodontitis.
10.1126/sciimmunol.aau4594
Understanding Scarring in the Oral Mucosa.
Advances in wound care
Skin inevitably heals with the formation of a fibrotic scar. Patients affected by skin scarring suffer from long-term psychological and physical burdens. Since the discovery of fetal scarless skin-wound healing, research has hoped to identify and mimic scarless healing for adult skin. Oral mucosa healing in adults provides the closest example to fetal scarless healing. Injuries to the oral mucosa heal with very minimal scarring. Understanding the mechanisms through which this process occurs may bring us closer to achieving scarless healing in adults. In this review, we summarize the current evidence that illustrates distinct mechanisms involved in oral mucosal healing. We discuss the role of the oral niche in contributing to wound repair. The intrinsic properties of immune cells, fibroblasts, and keratinocytes within the oral mucosa that support regenerative repair are provided. We highlight the contribution of cytokines, growth factors, and chemokine secretion in permitting a scarless mucosal environment. Furthermore, we discuss the role of stem cell-like progenitor populations in the mucosa that may contribute to wound healing. We also provide suggestions for future studies that are needed to achieve scarless healing in adults. Many characteristics of the oral mucosa have been shown to contribute to decreased scarring, but the specific mechanism(s) is unclear. Advancing our understanding of oral healing may yield therapeutic therapies that can be used to overcome dermal scarring.
10.1089/wound.2021.0038
Crosstalk between the oral microbiota, mucosal immunity, and the epithelial barrier regulates oral mucosal disease pathogenesis.
Mucosal immunology
Oral mucosal disease (OMD), which is also called soft tissue oral disease, is described as a series of disorders or conditions affecting the mucosa and soft tissue in the oral cavity. Its etiology is unclear, but emerging evidence has implicated the influence of the composition of the oral mucosa and saliva-resident microbiota. In turn, this dysbiosis effects the immune response balance and epithelial barrier function, followed by the occurrence and progression of OMD. In addition, oral microbial dysbiosis is diverse in different types of diseases and different disease progressions, suggesting that key causal pathogens may exist in various oral pathologies. This narrative literature review primarily discusses the most recent findings focusing on how microbial dysbiosis communicates with mucosal adaptive immune cells and the epithelial barrier in the context of five representative OMDs, including oral candidiasis (OC), oral lichen planus (OLP), recurrent aphthous ulcer (RAU), oral leukoplakia (OLK), and oral squamous cell carcinoma (OSCC), to provide new insight into the pathogenetic mechanisms of OMDs.
10.1038/s41385-021-00413-7
The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies.
Elad Sharon,Yarom Noam,Zadik Yehuda,Kuten-Shorrer Michal,Sonis Stephen T
CA: a cancer journal for clinicians
Oral mucositis (OM) is a common, highly symptomatic complication of cancer therapy that affects patients' function, quality of life, and ability to tolerate treatment. In certain patients with cancer, OM is associated with increased mortality. Research on the management of OM is ongoing. Oral mucosal toxicities are also reported in targeted and immune checkpoint inhibitor therapies. The objective of this article is to present current knowledge about the epidemiology, pathogenesis, assessment, risk prediction, and current and developing intervention strategies for OM and other ulcerative mucosal toxicities caused by both conventional and evolving forms of cancer therapy.
10.3322/caac.21704
Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity.
Cell
The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.
10.1016/j.cell.2021.05.013
Regional specification of oral mucosal immunity.
Science immunology
In this issue of , Barreto de Albuquerque track immune responsiveness to the foodborne pathogen during oral infection. Their findings extend the notion of compartmentalized immunity within the gastrointestinal tract to the oral cavity and provide previously unkown insights into regional specialization of oral immunity.
10.1126/sciimmunol.abp8632