Biology subjects

Kabat, A. M.

Publications and source records attributed to Kabat, A. M..

5 recordsLinked to original sources

bioRxiv2023

Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment

Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.

immunology↗

bioRxiv2022

HIGHLY PHAGOCYTIC LIPID-ASSOCIATED MACROPHAGES (LAMs) ARE INCREASED IN COLONIC LAMINA PROPRIA IN OBESITY

Little is known about the effects of high fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1hiMHCIIhi, and were CD4-TIM4-. During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid associated macrophages (LAMs). Via single cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HDF, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis and efferocytosis signatures. CX3CR1hiMHCIIhi colonic resident LPMs had fewer lipid droplets (LD) and decreased triacylglycerol (TAG) content compared to equivalent cells in lean mice, and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.

immunology↗

bioRxiv2022

In macrophages fatty acid oxidation spares glutamate for use in diverse metabolic pathways required for alternative activation

Fatty acid oxidation (FAO) is upregulated in IL-4-stimulated (alternatively activated) macrophages (M(IL-4)). We examined the effect of loss of function of the enzyme Cpt1a, which facilitates the entry of long chain fatty acids (FA) into mitochondria for FAO, on alternative activation. Expression of M(IL-4) markers ARG1, CD301 and RELM, was impaired in tamoxifen-treated ERT2Cre x Cpt1afl/fl macrophages and in macrophages expressing shRNA targeting Cpt1a (Cpt1a-shRNA). In contrast, VaviCre x Cpt1afl/fl and LysmCre x Cpt1afl/fl M(IL-4) responded normally to IL-4. Reduced alternative activation due to Cpt1a loss of function was linked to decreased cellular pools of -ketoglutarate, glutamate, and glutathione, diminished commitment of glucose carbon to serine/glycine synthesis, and decreased expression of genes in the Nrf2-oxidative stress response pathway. Consistent with this, reactive oxygen species were increased. Restoration of glutathione pools with N-acetyl cysteine normalized oxidative stress and allowed alternative activation in the face of Cpt1a-deficiency, pointing to a role for FAO in the control of ROS and as being important for alternative activation. In VaviCre x Cpt1afl/fl M(IL-4), glutamine uptake was increased, compensating for the loss of FAO to meet necessary metabolic demands, to allow alternative activation. The data indicate that macrophages are able to regulate glutamine metabolism to compensate for chronic disruption of FAO to meet metabolic needs.

immunology↗

bioRxiv2022

Resident T cells orchestrate adipose tissue remodeling in a site peripheral to infection

Infection with helminth parasites can affect adiposity, but underlying mechanisms that regulate this process are unclear. We found that fat content of mesenteric adipose tissue (mAT) declined in mice during infection with gut-restricted parasitic worms. This was associated with the accumulation of metabolically activated, immunostimulatory cytokine- and extracellular matrix-secreting multipotent stromal cells, which had potential to differentiate into preadipocytes. Concomitantly, mAT became infiltrated with Th2 lymphocytes that took up long-term residence and responded to signals from stromal cells by producing stromal cell-stimulating cytokines, including Amphiregulin. Signals delivered by Amphiregulin to stromal cells were required for immunity to infection. Our findings reveal intricate intercellular communication between Th2 cells and adipocyte progenitors and link immunity to intestinal infection to T cell-dependent effects on the adipocyte lineage.

immunology↗

bioRxiv2021

Predictive framework of macrophage activation

Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disjointed picture of macrophage biology that emerged from these observations are a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a striking commonality and finite number of transcriptional profiles, which we modelled as defined stages along four conserved activation paths. We verified this model with adoptive cell transfer experiments and identified transient RELM[a] expression as a feature of macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of macrophage activation in inflammation and homeostasis. One Sentence SummaryWe propose an integrative approach of macrophage classification that allows the establishment of a common framework of macrophage activation in inflammation and homeostasis.

immunology↗