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Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE205942 | GEO | 2022/12/28

REPOSITORIES: GEO

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Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin [CITE-seq]

Project description:Tissue-resident memory CD8+T (TRM) cells are a distinct component of the memory T cell armamentarium found in many tissues. Recent studies have shown disparities among TRM cells across tissues, but it is unknown whether there is heterogeneity among TRM cells from differentanatomic compartments of the small intestine and colon. Herewe show that intestinal TRM cells exhibit distinctive patterns of cytokine and granzyme expression, along with substantial transcriptional, epigenetic, and functional heterogeneity. We elucidate unexpected tissue- and context-specific regulatory roles for the T-box transcription factor Eomesodermin (Eomes), previously described to repressskin, liver, and kidney TRM cell formation, in promoting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of TRMcells from the small intestine and colon.

2022-12-28 | GSE205941 | GEO

Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin [scATAC-seq]

2022-12-28 | GSE205549 | GEO

Small intestine and colon tissue-resident memory CD8<sup>+</sup> T cells exhibit molecular heterogeneity and differential dependence on Eomes.

Project description:Tissue-resident memory CD8+ T (TRM) cells are a subset of memory T cells that play a critical role in limiting early pathogen spread and controlling infection. TRM cells exhibit differences across tissues, but their potential heterogeneity among distinct anatomic compartments within the small intestine and colon has not been well recognized. Here, by analyzing TRM cells from the lamina propria and epithelial compartments of the small intestine and colon, we showed that intestinal TRM cells exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional, epigenetic, and functional heterogeneity. The T-box transcription factor Eomes, which represses TRM cell formation in some tissues, exhibited unexpected context-specific regulatory roles in supporting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of intestinal TRM cells.

| S-EPMC9904390 | biostudies-literature

Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin

Project description:Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin

| PRJNA848394 | ENA

Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin [scATAC-seq]

| PRJNA846313 | ENA

Small intestine and colon tissue-resident memory CD8+ T cells exhibit transcriptional, epigenetic, and functional heterogeneity in concert with differential dependence on Eomesodermin [CITE-seq]

| PRJNA848395 | ENA

Resident memory CD8 T cells persist for years in human small intestine.

Project description:Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for >1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

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Mouse Memory CD8 T Cell Subsets Defined by Tissue-Resident Memory Integrin Expression Exhibit Distinct Metabolic Profiles.

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

Tissue-Resident Memory-Like CD8<sup>+</sup> T Cells Exhibit Heterogeneous Characteristics in Tuberculous Pleural Effusion.

Project description:Tissue-resident memory T (TRM) cells are well known to play critical roles in peripheral tissues during virus infection and tumor immunology. Our previous studies indicated that CD69+CD4+ and CD69+CD8+ T cells in tuberculous pleural effusion (TPE) were antigen-specific memory T cells. However, the phenotypical and functional characteristics of CD8+ TRM cells in tuberculosis remain unknown. We found that CD103+CD8+ T cells were the predominant subset of CD103+ lymphocytes in TPE; both CD103 and CD69 expressed on memory CD8+ T cells from TPE were significantly increased compared with those from paired peripheral blood. Phenotypically, CD103+CD69+ and CD103+CD69-CD8+ T cells expressed higher levels of CD45RO than CD103-CD69+CD8+ T cells did; CD103+CD69-CD8+ T cells highly expressed CD27, CD127, and CD62L and some chemokine receptors. We further compared the functional differences among the four distinct CD45RO+CD8+ T subsets identified by CD103 and CD69 expression. In consist with our published results, CD69+CD8+ T cells, but not CD103+CD8+, produced high levels of IFN-γ after treatment with BCG in the presence of BFA. Nevertheless, CD103-CD69+ and CD103+CD69+ memory CD8+ T cells expressed higher levels of Granzyme B, while CD103+CD69- memory CD8+ T cells were characterized as a possibly immunosuppressive subset by highly expressing CTLA-4, CD25, and FoxP3. Furthermore, TGF-β extremely increased CD103 expression but not CD69 in vitro. Together, CD103+CD8+ T cells form the predominant subset of CD103+ lymphocytes in TPE; CD103 and CD69 expression defines distinct CD8+ TRM-like subsets exhibiting phenotypical and functional heterogeneity. Our findings provide an important theoretical basis to optimize and evaluate new tuberculosis vaccines.

| S-EPMC8084674 | biostudies-literature

Tissue-Resident Macrophages Limit Pulmonary CD8 Resident Memory T Cell Establishment.

Project description:Tissue resident memory CD8 T cells (TRM) serve as potent local sentinels and contribute significantly to protective immunity against intracellular mucosal pathogens. While the molecular and transcriptional underpinnings of TRM differentiation are emerging, how TRM establishment is regulated by other leukocytes in vivo is largely unclear. Here, we observed that expression of PPAR-γ in the myeloid compartment was a negative regulator of CD8 TRM establishment following influenza virus infection. Interestingly, myeloid deficiency of PPAR-γ resulted in selective impairment of the tissue-resident alveolar macrophage (AM) compartment during primary influenza infection, suggesting that AM are likely negative regulators of CD8 TRM differentiation. Indeed, influenza-specific CD8 TRM cell numbers were increased following early, but not late ablation of AM using the CD169-DTR model. Importantly, these findings were specific to the parenchyma of infected tissue as circulating memory T cell frequencies in lung and TCM and TEM in spleen were largely unaltered following macrophage ablation. Further, the magnitude of the effector response could not explain these observations. These data indicate local regulation of pulmonary TRM differentiation is alveolar macrophage dependent. These, findings could aid in vaccine design aimed at increasing TRM density to enhance protective immunity, or deflating their numbers in conditions where they cause overt or veiled chronic pathologies.

| S-EPMC6797929 | biostudies-literature

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