Tissue-specific Immunity Research Articles

Inducible, but not constitutive, pancreatic REG/Reg isoforms are regulated by intestinal microbiota and pancreatic diseases.

The REG / Reg gene locus encodes for a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in human and mouse, pancreas and gut differed in REG / Reg isoform levels and preferences, with duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as "inducible" and others as "constitutive". Indeed, also in models of pancreatic-ductal adenocarcinoma and pancreatitis, only inducible Reg members were upregulated in pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG / Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.

Abstract 2698: TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma

Abstract Tissue-resident immune cells reside within the gastrointestinal tract known as intraepithelial lymphocytes (T-IELs), including αβ and γδ T-IELs. This unique population of T cells constantly survey and are critical in maintaining the gastrointestinal epithelium. We show that T-IELs in various regions of the gastrointestinal tract have distinct features. T-IELs in the small intestine exhibit high expression of cytotoxic molecules important for cancer defense while colon T-IELs are distinctively regulated by the transcription factor, TCF-7/TCF-1, which suppresses their effector and cytotoxic properties, including reduced expression of granzymes, and their abundance is dependent on the microbiome. Targeted deletion of TCF-1 in γδ T-IELs using pre-clinical mouse models resulted in a distinct effector profile and reduced colon tumor burden. Furthermore, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers compared with normal healthy colon, strongly correlating with an enhanced γδ T-IEL effector phenotype and improved patient survival. Further investigation aims to elucidate diverse mechanisms by which TCF-1 controls tissue-specific anti-tumor immunity and uncover the important factors controlling TCF-1 expression. Our study underscores the necessity to consider tumor and organ microenvironment-specific factors in optimizing immunotherapy, advancing our understanding of T cell function in the colon to pave the way for innovative CRC treatments. Citation Format: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke. TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2698.

Jen Gommerman: Leadership is not a one-way street.

Jen Gommerman is a Canada Research Chair in Tissue Specific Immunity, and a professor and newly appointed chair for the Department of Immunology at the University of Toronto. Her lab is interested in the underlying mechanisms of immune dysregulation in autoimmune diseases such as MS, mucosal immunology, and the role of TNF family members in immune cell biology. We spoke to Jen about the importance of authenticity and openness in leadership, and her goals as she begins her tenure as department chair of Immunology.

Lymph node sharing between pancreas, gut, and liver leads to immune crosstalk and regulation of pancreatic autoimmunity

Lymph nodes (LNs) are critical sites for shaping tissue-specific adaptive immunity. However, the impact of LN sharing between multiple organs on such tailoring is less understood. Here, we describe the drainage hierarchy of the pancreas, liver, and the upper small intestine (duodenum) into three murine LNs. Migratory dendritic cells (migDCs), key in instructing adaptive immune outcome, exhibited stronger pro-inflammatory signatures when originating from the pancreas or liver than from the duodenum. Qualitatively different migDC mixing in each shared LN influenced pancreatic β-cell-reactive Tcells to acquire gut-homing and tolerogenic phenotypes proportional to duodenal co-drainage. However, duodenal viral infections rendered non-intestinal migDCs and β-cell-reactive Tcells more pro-inflammatory in all shared LNs, resulting in elevated pancreatic islet lymphocyte infiltration. Our study uncovers immune crosstalk through LN co-drainage as a powerful force regulating pancreatic autoimmunity.

The diverse landscape of memory T-cell heterogeneity.

The diverse landscape of memory T-cell heterogeneity.

MRNA vaccination induces persistent pharyngeal mucosal B cell responses to SARS-CoV-2 in children

Abstract We recently reported that SARS-CoV-2 infection triggers robust, persistent adaptive immune responses in the tonsils and adenoids of children. However, whether mRNA vaccination induces similar immune responses and how this compares to natural infection in children are unknown. To evaluate these questions, we collected peripheral blood (PBMCs), tonsils, and adenoids from 30 children undergoing tonsillectomy/adenoidectomy primarily in 2022. From questionnaires and serology, we identified 12 vaccinated subjects who had not been infected and compared them to 24 COVID-19 convalescent children from our previous study collected in 2020–2021. We found SARS-CoV-2-specific germinal center and CD27 +switched memory B (B SM) cells, including cells recognizing the spike protein receptor binding domain (RBD) of the original WA-1 strain and RBD from Omicron, in pharyngeal tissues of vaccinated children. PBMCs trended towards having higher percentages of S1 +RBD +B cells post-vaccination than post-infection, while adenoids had more S1 +RBD +B cells post-infection. SARS-CoV-2-specific B SMcells were dominated by IgG isotypes in all tissues, but a higher proportion of IgA +cells were seen post-infection. Furthermore, S1 +RBD +B SMcells showed greater CXCR3 expression post-infection in all tissues. In contrast, S1 +RBD +B SMcells showed higher expression of activation and atypical markers post-vaccination, particularly in PBMCs, implying different characteristics of B cell memory depending on the type of exposure. Our results demonstrate tissue-specific immunity to SARS-CoV-2 in the upper respiratory tract of children after vaccination and provide further evidence that mRNA vaccination induces broad protective B cell memory. This work was supported in part by intramural funds of NIAID, NIH.

A shift in the hepatic immunological pattern from predominant adaptive immunity to innate immunity compromises tissue-specific immunity and leads to HCC

Abstract The incidence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is growing because of the global consumption of high fat, high sugar or Western diet (WD). Current data suggests a correlation between the hepatic inflammation and progression of NAFLD to HCC. However, contradictory reports on the identification of specific inflammatory cells or cytokines hinder further progress in the field. Such controversial reports are due to highly reductionist approaches and getting lost in the details. By using flow cytometry, we have demonstrated that the hepatic immunological patterns were associated with the progression or inhibition of HCC, which can be discovered through the detection of the proportion of immune cell types functioning as a network. However, flow cytometry utilizes a limited number of markers hindering a comprehensive detection of the patterns. Here, we perform scRNAseq of the liver collected from the mouse model of NAFLD (DIAMOND) being on a WD prior to or after the development of HCC, as well as control mice being on a chow diet (CD). We demonstrate that a WD alters the hepatic immunological pattern by dominating innate immunity, M1 macrophages, over adaptive immunity, B and T cells, associated with the activation of the hepatic fibroblasts. Each immunological pattern created a distinct collective function beyond the function of its cellular constituents. Also, shifts in the immunological pattern compromised the hepatic immune system, transforming its anti-tumor function to carcinogenesis-promoting process. Our data suggest that the discovery and modulation of the hepatic immunological pattern could offer a comprehensive understanding of and curative treatment for NAFLD and HCC. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense.This work was also supported, in part, by CTSA award No. UL1TR002649 from the National Center for Advancing Translational Sciences.

Violation of the vaginal microbiome and the risk of HIV infection in women

Women are the main population responsible for new HIV infections and the persistence of the HIV pandemic. The article provides a review of the current literature on the factors and mechanisms by which the vaginal microbiome can contribute to HIV infection. A key determinant of susceptibility to HIV infection is the composition of the vaginal microbiome, which can influence the local immune cell population and inflammation status. A low diversity microbial composition dominated by Lactobacillus crispatus does not increase the risk of HIV infection, and a high microbial diversity environment associated with bacterial vaginosis increases the risk of HIV infection. The female reproductive tract has a unique susceptibility to viral infection because tissue-specific immunity must elicit rapid antimicrobial responses to pathogens while maintaining sperm tolerance. It is important to note that the risk of HIV infection during sexual intercourse is multifactorial and is determined not only by the state of the microbiota of a woman’s genital tract, but also by the state of the partner’s microbiota, the viral load of HIV in the blood of the sexual partner, the presence/absence of anti-retroviral therapy in the partner, hormonal background and the phase of the menstrual cycle, which also affect the state of the microbiota.

Tissue specific imprinting on innate lymphoid cells during homeostasis and disease process revealed by integrative inference of single-cell transcriptomics.

Innate lymphoid cells (ILCs) are key components of the immune system, yet the similarity and distinction of the properties across tissues under homeostasis, inflammation and tumor process remain elusive. Here we performed integrative inference of ILCs to reveal their transcriptional profiles and heterogeneity from single-cell genomics. We collected a large number of ILCs from human six different tissues which can represent unique immune niches (circulation, lymphoid tissue, normal and inflamed mucosa, tumor microenvironment), to systematically address the transcriptional imprinting. ILCs are profoundly imprinted by their organ of residence, and tissue-specific distinctions are apparent under pathological conditions. In the hepatocellular carcinoma microenvironment, we identified intermediate c-kit+ ILC2 population, and lin-CD127- NK-like cells that expressed markers of cytotoxicity including CCL5 and IFNG. Additionally, CD127+CD94+ ILC1s were preferentially enriched in inflamed ileum from patients with Crohn's disease. These analyses depicted a comprehensive characterization of ILC anatomical distribution and subset heterogeneity, and provided a base line for future temporal or spatial studies focused on tissue-specific ILC-mediated immunity.

Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs.

Respiratory viral infections reprogram pulmonary macrophages with altered anti-infectious functions. However, the potential function of virus-trained macrophages in antitumor immunity in the lung, a preferential target of both primary and metastatic malignancies, is not well understood. Using mouse models of influenza and lung metastatic tumors, we show here that influenza trains respiratory mucosal-resident alveolar macrophages (AMs) to exert long-lasting and tissue-specific antitumor immunity. Trained AMs infiltrate tumor lesions and have enhanced phagocytic and tumor cell cytotoxic functions, which are associated with epigenetic, transcriptional and metabolic resistance to tumor-induced immune suppression. Generation of antitumor trained immunity in AMs is dependent on interferon-γ and natural killer cells. Notably, human AMs with trained immunity traits in non-small cell lung cancer tissue are associated with a favorable immune microenvironment. These data reveal a function for trained resident macrophages in pulmonary mucosal antitumor immune surveillance. Induction of trained immunity in tissue-resident macrophages might thereby be a potential antitumor strategy.

Tissue-resident memory T cells in renal autoimmune diseases.

The discovery of tissue-resident memory T cells (TRM cells) reinterpreted the potential of human tissue-specific immunity. Following T cell receptor (TCR) activation and clonal expansion, effector T cells migrate to peripheral tissues where they remain long-term and differentiate to TRM cells after antigen clearance. This allows for prompt immunological responses upon antigen re-encounter. In addition to their protective properties in acute infections, recent studies have revealed that TRM cells might lead to aggravation of autoimmune diseases, such as lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). These diseases present as proliferative and crescentic glomerulonephritis (cGN), which is a life-threatening condition leading to end-stage renal disease (ESRD) if left untreated. A better understanding of renal TRM cells might lead to identifying new therapeutic targets for relapsing autoimmune diseases of the kidney. In this review, we summarize the current knowledge of renal TRM cells and discuss their potential pathophysiological roles in renal autoimmune diseases.

Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children.

Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues. Expanded T cell clonotypes were found in tonsils, adenoids and blood post-COVID-19, some with CDR3 sequences identical to previously reported SARS-CoV-2-reactive T cell receptors (TCRs). Pharyngeal tissues from COVID-19-convalescent children showed persistent expansion of germinal center and antiviral lymphocyte populations associated with interferon (IFN)-γ-type responses, particularly in the adenoids, and viral RNA in both tissues. Our results provide evidence for persistent tissue-specific immunity to SARS-CoV-2 in the upper respiratory tract of children after infection.

Single-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity.

Knowledge of the transcriptional programs underpinning the functions of human kidney cell populations at homeostasis is limited. We present a single-cell perspective of healthy human kidney from 19 living donors, with equal contribution from males and females, profiling the transcriptome of 27677 cells to map human kidney at high resolution. Sex-based differences in gene expression within proximal tubular cells were observed, specifically, increased anti-oxidant metallothionein genes in females and aerobic metabolism-related genes in males. Functional differences in metabolism were confirmed in proximal tubular cells, with male cells exhibiting higher oxidative phosphorylation and higher levels of energy precursor metabolites. We identified kidney-specific lymphocyte populations with unique transcriptional profiles indicative of kidney-adapted functions. Significant heterogeneity in myeloid cells was observed, with a MRC1+LYVE1+FOLR2+C1QC+ population representing a predominant population in healthy kidney. This study provides a detailed cellular map of healthy human kidney, and explores the complexity of parenchymal and kidney-resident immune cells.

A First Step Toward a Cross-tissue Atlas of Immune Cells in Humans.

A First Step Toward a Cross-tissue Atlas of Immune Cells in Humans.

Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells.

The cytokine interleukin-23 (IL-23) is critical for development and maintenance of autoimmune inflammation in nonlymphoid tissues; however, the mechanism through which IL-23 supports tissue-specific immunity remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from Candida albicans skin infection, and tissue-resident memory (TRM) cell-mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23 receptor antibody to mice after resolution of primary C. albicans infection resulted in loss of CD69+ CD103+ tissue-resident memory T helper 17 (TRM17) cells from skin, and clinical anti-IL-23 therapy depleted TRM17 cells from skin of patients with psoriasis. IL-23 receptor blockade impaired TRM17 cell proliferation but did not affect apoptosis susceptibility or tissue egress. IL-23 produced by CD301b+ myeloid cells was required for TRM17 maintenance in skin after C. albicans infection, and CD301b+ cells were necessary for TRM17 expansion during the development of imiquimod dermatitis. This study demonstrates that locally produced IL-23 promotes in situ proliferation of cutaneous TRM17 cells to support their longevity and function and provides mechanistic insight into the durable efficacy of IL-23 blockade in the treatment of psoriasis.

Tissue-specific immunity

Tissue-specific immunity

Examining multi-level immune response to determine prevalence of COVID-19 in pediatric tonsillectomy.

ObjectiveTo determine the prevalence of COVID‐19 in a cohort of children undergoing tonsillectomy through assessment of B cell immune responses to SARS‐CoV‐2 in both peripheral blood and tonsil tissue.MethodsIn this cohort study at a tertiary pediatric hospital (Children's National Hospital) in Washington, DC, we recruited 100 children undergoing tonsillectomy from late September 2020 to January 2021. Serum, peripheral blood cells, and tonsil tissue were collected and examined for immune reactivity to SARS‐CoV‐2. Parent‐reported clinical histories were compared to antibody and B‐cell responses.ResultsAmong 100 children undergoing tonsillectomy, 19% had evidence of immune responses to SARS‐CoV‐2 (CoV2+), indicating prior COVID‐19. In all seropositive participants, we detected SARS‐CoV‐2 specific B cells in both peripheral blood mononuclear cells and tonsils, providing evidence for tissue‐specific immunity in these children. Of the 19, 63% reported no known history of COVID‐19, and an additional 3 were asymptomatic or unaware of an acute infection when detected on pre‐surgery screen. Hispanic children represented 74% of CoV2+ subjects compared to 37% of the full cohort. 100% of CoV2+ children lived in a zip code with poverty level >10%.ConclusionsNearly one‐fifth of children undergoing tonsillectomy at an urban U.S. hospital had evidence of prior COVID‐19 during the early pandemic, with the majority unaware of prior infection. Our results underscore the ethnic and socio‐economic disparities of COVID‐19. We found concordant evidence of humoral immune responses in children in both blood and tonsil tissue, providing evidence of local immune responses in the upper respiratory tract.Level of Evidence3 Laryngoscope, 2022

Neuroendocrine regulations in tissue-specific immunity: From mechanism to applications in tumor.

Immune responses in nonlymphoid tissues play a vital role in the maintenance of homeostasis. Lots of evidence supports that tissue-specific immune cells provide defense against tumor through the localization in different tissue throughout the body, and can be regulated by diverse factors. Accordingly, the distribution of nervous tissue is also tissue-specific which is essential in the growth of corresponding organs, and the occurrence and development of tumor. Although there have been many mature perspectives on the neuroendocrine regulation in tumor microenvironment, the neuroendocrine regulation of tissue-specific immune cells has not yet been summarized. In this review, we focus on how tissue immune responses are influenced by autonomic nervous system, sensory nerves, and various neuroendocrine factors and reversely how tissue-specific immune cells communicate with neuroendocrine system through releasing different factors. Furthermore, we pay attention to the potential mechanisms of neuroendocrine-tissue specific immunity axis involved in tumors. This may provide new insights for the immunotherapy of tumors in the future.

A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins.

To understand functional duality of the complement system in host defense and lung injury, a more comprehensive view of its localized production in the lung, and the impact of age on complement production are essential. Here, we explored the expression of complement genes through computational analysis of preexisting single cell RNA sequencing data from lung transcriptomes of healthy young (3 months) and old C57BL/6 mice (24 months), and humans. We characterized the distribution of 48 complement genes. Across 28 distinct immune and non-immune cell types in mice, mesothelial cells expressed the greatest number of complement genes (e.g., C1ra, C2, C3), and regulators (e.g., Serping1, Cfh). C5 was abundant in type II alveolar epithelial cells and C1q in interstitial lung macrophages. There were only moderate differences in gene expression between young and old mice. Among 57 human lung cell types, mesothelial cells showed abundant complement expression. A few differences in gene expression (e.g., FCN1, CFI, C6, C7) were also evident between mice and human lung cells. Our findings present a novel perspective on the expression patterns of complement genes in normal lungs. These findings highlight the potential functions of complement in tissue-specific homeostasis and immunity and may foster a mechanistic understanding of its role in lung health and disease.

SARS-CoV-2 Virion Infectivity and Cytokine Production in Primary Human Airway Epithelial Cells.

The emergence of new SARS-CoV-2 variants and the replacement of preceding isolates have been observed through B.1.1.7, B.1.351, B.1.617.2, and B.1.1.529 lineages (corresponding to alpha, beta, delta, and omicron variants of concern (VoC), respectively). However, there is still a lack of biological evidence to which extent those VoC differ from the ancestral lineages. By exploiting human airway epithelial cell (HAEC) cultures, which closely resemble the human airway architecture and physiology, we report distinctive SARS-CoV-2 tropism in different respiratory tissues. In general, SARS-CoV-2 VoC predominantly infect and replicate in HAEC better than the progenitor USA-WA1 isolate or the BavPat1 isolate, which contains the D614G mutation, even though there is little to no difference between variants regarding their infectivity (i.e., virion-per-vRNA copy ratio). We also observe differential tissue-specific innate immunity activation between the upper and lower respiratory tissues in the presence of the virus. Our study provides better comprehension of the behavior of the different VoC in this physiologically relevant ex vivo model.