A characteristic of memory T (T M ) cells is their ability to mount faster and stronger responses to reinfection than naïve T (T N ) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 T M cells have more mitochondrial mass than CD8 T N cells and, that upon activation, the resulting secondary effector T (T E ) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, T M cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than T N cells, suggesting that greater mitochondrial mass in T M cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both T N and T M cells. We also found that fatty acid oxidation is needed for T M cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in T M cells. Our results demonstrate that greater mitochondrial mass endows T M cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection.

Bioenergetics

Anaerobic glycolysis

Hexokinase

10.1073/pnas.1221740110

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Citations (477)

TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

PLoS Pathogens (2016)

Yashaswini Kannan Jimena Perez-Lloret Yanda Li Lewis J. Entwistle Hania Khoury

Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8–/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8–/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis.

10.1371/journal.ppat.1005783

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Citations (24)

The transcription factor Bhlhe40 is a novel regulator of large peritoneal macrophages and type 2 immunity

The Journal of Immunology (2018)

Nicholas N. Jarjour Tara R. Bradstreet Elizabeth A. Schwarzkopf Chih‐Chung Lin Melissa E. Cook

Abstract Tissue-resident macrophages occupy key roles in immunity and physiology within organ microenvironments. Many tissue macrophages derive from embryonic progenitors and self-maintain locally as unique tissue-specific populations. Resident macrophages can also expand in response to type 2 stimuli including parasites and contribute to control of infection via the alternative activation program. However, the transcriptional basis for this capacity to proliferate in situ is poorly understood. We have observed that the transcription factor basic helix-loop-helix, member e40 (Bhlhe40) is highly expressed in a subset of hematopoietic cell types, including large peritoneal macrophages (LPMs). Based on this data, we hypothesized that Bhlhe40 is a key part of the LPM transcriptional network. We have found that peritoneal macrophages are selectively reduced in Bhlhe40−/− mice, in contrast to other resident macrophages. Mixed bone marrow chimeras, conditional knockout mice, and other approaches demonstrated a specific, intrinsic defect in mature, Bhlhe40-deficient LPMs. Bhlhe40−/− LPMs exhibited an alternative activation-like profile and impaired self-renewal. These functional perturbations were correlated with altered expression of gene sets pertaining to the endoplasmic reticulum (ER) and protein homeostasis, as well as ER morphology changes in Bhlhe40−/− LPMs. Using models of peritoneal type 2 immunity, we observed near-total loss of expansion of Bhlhe40-deficient LPMs, correlated with impaired control of an intestinal helminth. Our findings demonstrate critical roles for Bhlhe40 as a tissue-specific regulator of resident macrophage self-renewal and expansion during type 2 immunity.

10.4049/jimmunol.200.supp.52.38

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Citations (1)

Fatty Acid Oxidation Is Essential for Egg Production by the Parasitic Flatworm Schistosoma mansoni

PLoS Pathogens (2012)

Stanley Ching‐Cheng Huang Tori C. Freitas Eyal Amiel Bart Everts Erika L. Pearce

Schistosomes, parasitic flatworms that cause the neglected tropical disease schistosomiasis, have been considered to have an entirely carbohydrate based metabolism, with glycolysis playing a dominant role in the adult parasites. However, we have discovered a close link between mitochondrial oxygen consumption by female schistosomes and their ability to produce eggs. We show that oxygen consumption rates (OCR) and egg production are significantly diminished by pharmacologic inhibition of carnitine palmitoyl transferase 1 (CPT1), which catalyzes a rate limiting step in fatty acid β-oxidation (FAO) and by genetic loss of function of acyl CoA synthetase, which complexes with CPT1 and activates long chain FA for use in FAO, and of acyl CoA dehydrogenase, which catalyzes the first step in FAO within mitochondria. Declines in OCR and egg production correlate with changes in a network of lipid droplets within cells in a specialized reproductive organ, the vitellarium. Our data point to the importance of regulated lipid stores and FAO for the compartmentalized process of egg production in schistosomes.

Carnitine O-palmitoyltransferase

Lipid droplet

Schistosoma

10.1371/journal.ppat.1002996

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Citations (53)

(830)

Journal of Pain (2007)

Stanley Ching‐Cheng Huang Marion Good Jeffrey M. Albert

Relaxation Therapy

10.1016/j.jpain.2007.02.237

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Citations (2)