Biology subjects

Lambert Emo, K.

Publications and source records attributed to Lambert Emo, K..

3 recordsLinked to original sources

bioRxiv2022

Mouse lung Tissue Resident Memory (TRM) CD8 T cell subsets have distinct metabolic profiles from each other and from non-TRM

Tissue-resident memory CD8 T cells (TRM) principally reside in peripheral non-lymphoid 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 TRM cells 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 utilize unique metabolic programs. To test this, differential expression and pathway analysis were conducted on RNAseq datasets from mouse lung TRM 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 cells subsets defined by integrin-expression in the lung have unique metabolic profiles and that nutrient abundance can alter differentiation.

immunology↗

bioRxiv2022

Fluximplied: A novel approach integrates rate limiting steps and differential expression for pathway analysis

BackgroundMany tools exist to perform a rigorous pathway analysis, though traditional gene set enrichment analysis remains among the most common. While useful for many applications, one common situation where it is less so is the metabolic profiling of bulk omics datasets. Rate limiting steps in more linear pathways are the main determinant of flux through these pathways, but differential expression of the enzymes that catalyze these steps is usually not differentially weighted in pathway analysis. Fluximplied was built to perform pathway analysis with rate limiting steps in mind to assess the implied flux through a number of well validated metabolic pathways. ResultsA database of rate limiting steps and their associated pathway was constructed. Using publicly available human RNA sequencing data from liver, putamen, and adipose tissue, fluximplied generally corroborated the pathway analysis. When comparing two CD8 T cell subsets from mouse lung, our algorithm confirmed previous findings that were not found previously. ConclusionFluximplied is an accessible tool for pathway analysis which is intended to assist the user with hypothesis generation. Unlike traditional approaches to pathway analysis, it specifically queries a database of rate limiting steps in order to infer flux through canonical metabolic pathways.

bioinformatics↗

bioRxiv2021

CD49a Identifies Polyfunctional Memory CD8 T cell Subsets that Persist in the Lungs after Influenza Infection

CD8 T cell memory offers critical antiviral protection, even in the absence of neutralizing antibodies. The paradigm is that CD8 T cell memory within the lung tissue consists of a mix of circulating TEM cells and non-circulating TRM cells. However, based on our analysis, the heterogeneity within the tissue is much higher, identifying TCM, TEM, TRM, and a multitude of populations which do not perfectly fit these classifications. Further interrogation of the populations shows that TRM cells that express CD49a, both with and without CD103, have increased and diverse effector potential compared with CD49a negative populations. These populations function as a one-man band, displaying antiviral activity, chemokine production, release of GM-CSF, and the ability to kill specific targets in vitro with delayed kinetics compared with effector CD8 T cells. Together, this study establishes that CD49a defines multiple polyfunctional CD8 memory subsets after clearance of influenza infection, which act to eliminate virus in the absence of direct killing, recruit and mature innate immune cells, and destroy infected cells if the virus persists. Contribution to the fieldProtection from previously seen infections requires specialized immune memory cells properly positioned throughout the body to combat the newly invading pathogen. In the case of re-exposure to influenza virus, CD8 T cells resident within the respiratory tract (TRM) are critical for eliminating the virus. Previously, TRM were viewed as mostly homogenous, with a limited range of immune functions. In this study, lung TRM were compared with circulating memory CD8 T cells transiently present within the lung, to define the breadth of their effector capabilities. Using TRM defining surface proteins CD49a and CD103 to identify different memory CD8 T cell subsets, gene and protein expression were evaluated. In addition to demonstrating higher levels of diversity than previously reported, multiple polyfunctional subsets were identified. This polyfunctionality was primarily associated with cell populations expressing CD49a, and these cells produced multiple antiviral factors, chemokines to recruit other immune cells, a growth factor associated with improved antigen presenting cell function, and cytolytic granules. Functional assays further demonstrated killing of target cells by TRM. This study paints a more holistic, complete picture of the phenotype and functions of lung CD8 T cells after viral infection, revealing CD49a as a marker of cells with high effector capacity.

immunology↗