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Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human TRM cells through study of donor-derived TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8+ TRM phenotypes. CD8+ CD69+CD103+ TRM cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrin+CD69+CD103- TRM cells have higher granzyme expression. Analysis of intestinal CD4+ T cells identifies several parallels, including a β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
| S-EPMC7816164 | biostudies-literature
Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating these two CD8+ populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft and lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while β2-integrin+ CD69+ CD103- TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
2020-12-05 | GSE162686 | GEO
Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating these two CD8+ populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft and lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while β2-integrin+ CD69+ CD103- TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
2020-12-05 | GSE162685 | GEO
Project description:Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets
| PRJNA682612 | ENA
Project description:Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets II
| PRJNA682615 | ENA
Project description:Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets I
| PRJNA682613 | ENA
Project description:Intestinal tissue-resident memory CD8 T cells (Trm) are non-recirculating effector cells ideally positioned to detect and react to microbial infections in the gut mucosa. There is an emerging understanding of Trm cell differentiation and functions, but their implication in inflammatory bowel diseases, such as Crohn's disease (CD), is still unknown. Here, we describe CD8 cells in the human intestine expressing KLRG1 or CD103, two receptors of E-cadherin. While CD103 CD8 T cells are present in high numbers in the mucosa of CD patients and controls, KLRG1 CD8 T cells are increased in inflammatory conditions. Mucosal CD103 CD8 T cells are more responsive to TCR restimulation, but KLRG1 CD8 T cells show increased cytotoxic and proliferative potential. CD103 CD8 T cells originate mostly from KLRG1 negative cells after TCR triggering and TGFβ stimulation. Interestingly, mucosal CD103 CD8 T cells from CD patients display major changes in their transcriptomic landscape compared to controls. They express Th17 related genes including CCL20, IL22, and IL26, which could contribute to the pathogenesis of CD. Overall, these findings suggest that CD103 CD8 T cells in CD induce a tissue-wide alert increasing innate immune responses and recruitment of effector cells such as KLRG1 CD8 T cells.
| S-EPMC7235448 | biostudies-literature
Project description:Alveolar macrophages (AMs) are functionally important innate cells involved in lung homeostasis and immunity and whose diversity in health and disease is a subject of intense investigations. Yet, it remains unclear to what extent conditions like smoking or chronic obstructive pulmonary disease (COPD) trigger changes in the AM compartment. Here, we aimed to explore heterogeneity of human AMs isolated from healthy nonsmokers, smokers without COPD, and smokers with COPD by analyzing BAL fluid cells by flow cytometry and bulk and single-cell RNA sequencing. We found that subpopulations of BAL fluid CD206+ macrophages could be distinguished based on their degree of autofluorescence in each subject analyzed. CD206+ autofluorescenthigh AMs were identified as classical, self-proliferative AM, whereas autofluorescentlow AMs were expressing both monocyte and classical AM-related genes, supportive of a monocytic origin. Of note, monocyte-derived autofluorescentlow AMs exhibited a functionally distinct immunoregulatory profile, including the ability to secrete the immunosuppressive cytokine IL-10. Interestingly, single-cell RNA-sequencing analyses showed that transcriptionally distinct clusters of classical and monocyte-derived AM were uniquely enriched in smokers with and without COPD as compared with healthy nonsmokers. Of note, such smoking-associated clusters exhibited gene signatures enriched in detoxification, oxidative stress, and proinflammatory responses. Our study independently confirms previous reports supporting that monocyte-derived macrophages coexist with classical AM in the airways of healthy subjects and patients with COPD and identifies smoking-associated changes in the AM compartment that may favor COPD initiation or progression.
| S-EPMC9348561 | biostudies-literature
Project description:Despite the obvious inhibitory outcome of PD-1 signaling, an additional series of functions are activated. We have observed that T cells stimulated through the T cell receptor (TCR) and PD-1 primarily do not proliferate; however, there is a population of cells that proliferates more than through TCR stimulation alone. In this study, we performed flow cytometry and RNA sequencing on individual populations of T cells and discovered that unlike naive T cells, which were inhibited following PD-1 ligation, T cells that proliferated more following PD-1 ligation were associated with effector and central memory phenotypes. We showed that these populations had different gene expression profiles following PD-1 ligation with PD-L1 compared to PD-L2. The presence of transcriptionally and functionally distinct T cell populations responsive to PD-1 ligation provides new insights into the biology of PD-1 and suggest the use of T cell subset-specific approaches to improve the clinical outcome of PD-1 blockade.
| S-EPMC8426269 | biostudies-literature
Project description:Tissue-resident memory CD8 T cells (TRM) principally reside in peripheral nonlymphoid tissues, such as lung and skin, and confer protection against a variety of illnesses ranging from infections to cancers. The functions of different memory CD8 T cell subsets have been linked with distinct metabolic pathways and differ from other CD8 T cell subsets. For example, skin-derived memory T cells undergo fatty acid oxidation and oxidative phosphorylation to a greater degree than circulating memory and naive cells. Lung TRMs defined by the cell-surface expression of integrins exist as distinct subsets that differ in gene expression and function. We hypothesize that TRM subsets with different integrin profiles will use unique metabolic programs. To test this, differential expression and pathway analysis were conducted on RNA sequencing datasets from mouse lung TRMs yielding significant differences related to metabolism. Next, metabolic models were constructed, and the predictions were interrogated using functional metabolite uptake assays. The levels of oxidative phosphorylation, mitochondrial mass, and neutral lipids were measured. Furthermore, to investigate the potential relationships to TRM development, T cell differentiation studies were conducted in vitro with varying concentrations of metabolites. These demonstrated that lipid conditions impact T cell survival, and that glucose concentration impacts the expression of canonical TRM marker CD49a, with no effect on central memory-like T cell marker CCR7. In summary, it is demonstrated that mouse resident memory T cell subsets defined by integrin expression in the lung have unique metabolic profiles, and that nutrient abundance can alter differentiation.
| S-EPMC10615656 | biostudies-literature