Jeffrey C. Rathmell’s research while affiliated with Vanderbilt University and other places

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Publications (357)


Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis
  • Preprint

January 2025

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4 Reads

Matthew T. Stier

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Allison E. Sewell

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Erin L. Mwizerwa

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[...]

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Jeffrey C. Rathmell

Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults. CD4 T cells in critical illness showed increased subset-specific metabolic plasticity, with regulatory T cells (Tregs) acquiring glycolytic capacity that stabilized suppressive markers FOXP3 and TIGIT and correlated with clinical illness severity. Single-cell transcriptomics identified differential kynurenine metabolism in Tregs, which was validated ex vivo as a mechanism of Treg glycolytic adaptation and suppressive rewiring. These findings underscore immunometabolic dysfunction as a driver of CD4 T cell remodeling in sepsis and suggest therapeutic avenues to restore an effective immune response.


Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations

January 2025

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6 Reads

Cancer Research

Obesity is an established risk factor for breast cancer development and poor prognosis. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression, and TREM2, a transmembrane receptor expressed on macrophages in adipose tissue and tumors, is an emerging therapeutic target for cancer. A better understanding of the mechanisms for the obesity-breast cancer association and the potential benefits of weight loss could help inform treatment strategies. Here, we utilized lean, obese, and weight loss mouse models to examine the impacts of TREM2 deficiency (Trem2+/+ and Trem2-/-) on postmenopausal breast cancer depending on weight history conditions. Trem2 deficiency constrained tumor growth in lean, but not obese or weight loss, mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed differences in the immune landscapes across the different models. Tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, anti-PD-1 therapy restricted tumor growth in lean and weight loss, but not obese, mice. These findings indicate that weight history could impact the efficacy of TREM2 inhibition in postmenopausal breast cancer. The reported immunological interactions between tumors and the surrounding adipose tissue highlight significant differences under obese and weight loss conditions.


Impaired oxidative phosphorylation drives primary tumor escape and metastasis

January 2025

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19 Reads

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.


A common ancestor in patients with the G6PC3c.210delC mutation.(A) Familial segregation of the mutation in four unrelated, non-consanguineous families. WT: wild type; M: mutant. (B) Sanger sequencing results of a healthy control and patient 1 (P1) in the region spanning the G6PC3 c.210delC mutation. Amino acid changes resulting from the mutation are annotated above the graphs. (C) Age estimation for the G6PC3 c.210delC variant, based on the lengths of shared ancestral haplotype blocks upstream and downstream of the G6PC3 frameshift allele (marked in red on chr17). The computationally inferred haplotypes from Father 3 (P3-F) and Father 4 (P4-F) are denoted with an asterisk
The G6PC3 c.210delC mutation is estimated to be of indigenous American ancestry. Principal component analysis (PCA) of ancestry on (A) the whole genome for c.210delC mutation carriers, using reference genomes from the combined 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP) dataset, and (B) on chromosome 17. (C) Local ancestry estimation across carriers of the c.210delC variant. The mutation locus (chr17:44,071,175) is marked in red on chromosome 17. Mutated alleles are labeled with red asterisks. AFR: African ancestry; AMR: Admixed American ancestry; EUR: European ancestry
The G6PC3 c.210delC mutation leads to a complete loss of protein expression. Schematic representation of (A)the G6PC3 gene with each box representing an exon and the mutation indicated in red, and (B) the G6PC3 protein structure with nine transmembrane domains in the endoplasmic reticulum. Red stars indicate the active site. The lower panel shows the predicted consequence of the c.210delC (p.F71Sfs*46) mutation. The out-of-frame sequence resulting from the premature stop codon is indicated in red. CP: cytoplasm; L: lumen. (C) RT-qPCR of G6PC3 mRNA expression in HEK293T cells either non-transfected (NT), transfected with the empty vector (EV), or transfected with plasmids encoding wildtype (WT) or F71Sfs*46 (M) G6PC3 with a 6xHis tag at either the N- or C-terminal. GUS was used as a control for gene expression. n = 3. (D) Western blotting of transfected HEK293T cell lysates using an anti-His Tag antibody. GAPDH was used as a loading control. (E) RT-qPCR of G6PC3 mRNA expression in EBV-B cells from patients and healthy controls. Data are presented as mean ± SD and represent three independent experiments. ***p ≤ 0.001 in a Student’s t-test. (F) G6PC3 protein expression by western blotting in membrane protein fraction of EBV-B cells. ATP1A1 was used as a membrane protein loading control
Impaired glycolysis in cells from G6PC3-deficient patients.(A) Measurement of extracellular acidification rate (ECAR) in response to glucose (gluc), ATP synthase inhibitor oligomycin (oligo), and glycolytic inhibitor 2-deoxy-glucose (2-DG) in EBV-B cells from two patients (P) and four healthy controls (HC) pretreated with 2-DG or 1,5-AG. (B) Quantification of glycolysis rate and glycolytic capacity in EBV-B cells from four healthy controls and two patients. (C) Western blotting analysis of LAMP2 glycosylation pattern in EBV-B cells. Cells were left untreated (UT), or treated with 2-DG or 1,5-AG for five days before the preparation of whole cell lysates. GAPDH was used as a loading control. Data are presented as mean ± SD and represent three independent experiments. Statistical analysis was performed using two-way ANOVA with Šidák correction. ***p ≤ 0.001, ****p ≤ 0.0001
Frequencies of the most prominent clinical features observed in G6PC3-deficient patients with the c.210delC mutation (n = 14) and those with other mutations (n = 112)
Molecular and Clinical Characterization of a Founder Mutation Causing G6PC3 Deficiency
  • Article
  • Full-text available

December 2024

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26 Reads

Journal of Clinical Immunology

G6PC3 deficiency is a monogenic immunometabolic disorder that causes severe congenital neutropenia type 4. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican descent. Based on the shared haplotypes amongst mutation carriers, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it appeared in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived Epstein-Barr Virus-immortalized B (EBV-B) cells. The neutropenia observed in G6PC3-deficient patients is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the c.210delC variant impacts glycolysis by performing extracellular flux assays on patient-derived EBV-B cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3-deficient patients reported in the literature, and we found that the c.210delC carriers display all prominent clinical features observed in prior patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-024-01836-0.

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Temporal recording of mammalian development and precancer

October 2024

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81 Reads

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2 Citations

Nature

Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3–5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell types and new epithelial progenitor states by their unique genetic histories. Analysis of mouse adenomas, coupled to multiomic and single-cell profiling of human precancers, with clonal analysis of 418 human polyps, demonstrated the occurrence of polyclonal initiation in 15–30% of colonic precancers, showing their origins from multiple normal founders. Our study presents a multimodal framework that lays the foundation for in vivo recording, integrating synthetic or natural indelible genetic changes with single-cell analyses, to explore the origins and timing of development and tumorigenesis in mammalian systems.


Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation

October 2024

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21 Reads

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1 Citation

The Journal of clinical investigation

Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.


Trem2 deficiency attenuates breast cancer tumor growth in lean, but not obese or weight loss, mice and is associated with alterations of clonal T cell populations

September 2024

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26 Reads

Obesity is an established risk factor for breast cancer development and worsened prognosis; however, the mechanisms for this association - and the potential benefits of weight loss - have not been fully explored. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression. An emerging therapeutic target for cancer is TREM2, a transmembrane receptor of the immunoglobulin superfamily that is expressed on macrophages in adipose tissue and tumors. We utilized genetic loss of function ( Trem2 +/+ and Trem2 -/- ) models and dietary (lean, obese, and weight loss) intervention approaches to examine impacts on postmenopausal breast cancer. Remarkably, Trem2 deficiency ameliorated tumor growth in lean, but not obese or weight loss mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mAT Tum-adj ) immune cells, revealed that tumors of lean Trem2 -/- mice exhibited a shift in clonal CD8 ⁺ T cells from an exhausted to an effector memory state, accompanied with increased clonality of CD4 ⁺ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mAT Tum-adj of the same mouse. Finally, an immune checkpoint study demonstrated that αPD-1 therapy restricted tumor growth in lean and weight loss, but not obese mice. We conclude that weight history is relevant when considering potential efficacy of TREM2 inhibition in postmenopausal breast cancer. This work reveals immunological interactions between tumors and surrounding adipose tissue, highlighting significant differences under obese and weight loss conditions.


Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation

September 2024

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40 Reads

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4 Citations

Science Immunology

Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (T H 1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many T H 1 cells subjected to such temperatures died, surviving T H 1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to T H 1 cells. T H 1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of T H 1 cells to maintain genomic integrity and enhance effector functions.


Citations (46)


... Adenomas represent the earliest recognized stage of tumour formation that leads to cancer in patients, but few profiling studies have been performed. However, human analyses accompanying this study confirm that polyps arising from genetic predisposition or sporadically frequently have complex clonal origins 39 . The degree to which polyclonal polyps have an increased risk of developing into carcinomas remains uncertain but their larger size already accommodates one such risk factor 40 . ...

Reference:

Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis
Temporal recording of mammalian development and precancer

Nature

... In this issue of the JCI, Chowdhury et al. address this knowledge gap head on, investigating how biological sex shapes T cell metabolism and function in the context of allergic airway inflammation (10). The study offers compelling evidence that androgen signaling fundamentally alters T helper 17 (Th17) cell metabolism, providing mechanistic insight into sex differences in allergic responses and potentially broader implications for autoimmune disease susceptibility. ...

Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation

The Journal of clinical investigation

... After treatment with heavy labeled glutamine, cells were washed with PBS, pelleted, flash frozen in liquid nitrogen, and stored at -80°. Metabolites were extracted, spiked with 100 nmol 13 C-1-Lactate (internal standard), and precipitated protein was dried under nitrogen as previously described (65). ...

Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities
  • Citing Article
  • August 2024

Science Immunology

... These studies aim to understand the development of EC and its relationship with inflammatory factors and tumorigenesis [135]. However, the relationship between obesity, immunity, and tumors remains unclear [136]. Some studies have investigated the impact of weight management on inflammatory factors and their subsequent influence on the immune microenvironment and EC development [137]. ...

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity

Nature

... Recent studies suggest that HSD may impact cancer progression through various mechanisms, including modulation of immune responses, changes in the composition of the gut flora, and the promotion of inflammation ( Figure 1). It has been demonstrated that chronic HSD increase the frequency of tumor-initiating stem cells (TISCs), enhance the expression of CD80 on the surface of TGF-b-mediated TISCs, weaken the antitumor response of CD8+ T and CD4+ T cells, and elevate the levels of CTLA4, a marker of immune depletion, which is associated with an increase in immune depletion (29). In an in vivo HSD model in MMTV-PyVT mice with spontaneous tumor-forming properties, HSD was found to promote breast cancer development and lung metastasis, and to increase the frequency of circulating Th17 cells. ...

Chronic High-Salt Diet Activates Tumor-Initiating Stem Cells Leading to Breast Cancer Proliferation

Cells

... While glucose competition is regularly cited as a key immunosuppressive mechanism in the TME [12] , data supporting this in human tumors is scarce. In renal cell carcinoma, glucose concentrations are similar between tumor interstitial fluid (~0.5-4 mM) and normal kidney interstitial fluid (~0.5-1.5 mM) [13][14][15] . Further, the widespread use of positron emission tomography scans to trace tumors supports the argument that glucose may not be limiting in human tumors, although this is likely to be patient and cancer dependent. ...

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability

eLife

... The efficacy of immunotherapies can be improved by enhancing the host immunity via mediation of metabolism [78]. Metabolism, such as glucose, lactate, and fatty acid metabolism, can regulate the regulatory T cell functions, which can be targeted for cancer immunotherapy [79]. Thus, the immunotherapy response can be boosted. ...

Cancer cell metabolism and antitumour immunity
  • Citing Article
  • April 2024

Nature Reviews Immunology

... One promising diagnostic strategy may be based on the discovery that early ccRCC shared common serum/urinary inflammatory signatures with chronic kidney disease (CKD). Indeed, mounting evidence has implicated tissue inflammation in the tumorigenesis of ccRCC [19][20][21][22][23], and CKD has proved an important risk factor for ccRCC [24,25]. However, accessible methods that can differentiate inflammatory kidney disease and early kidney cancer remain elusive. ...

VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis

The Journal of clinical investigation

... Starting from the reprogramming of lipid metabolism, identifying new targets to improve the efficacy of immunotherapy is a promising approach in precision tumor treatment and has the potential to enhance the efficacy of immunotherapy [37]. Tumor cells evade surveillance and attack by the immune system by changing their metabolic characteristics, which also affects the ability of immune cells to recognize and eliminate tumors [38]. Therefore, reprogramming of immune cell metabolism has been described as a new hallmark of tumors. ...

Immunometabolic Maladaptations to the Tumor Microenvironment
  • Citing Article
  • March 2024

Cold Spring Harbor Perspectives in Medicine

... Histone lactylation is a posttranslational modification that regulates gene expression by covalently attaching lactate groups to lysine residues on proteins. Lactylation plays a role in various physiological and pathological processes [50]. AML cells use lactate as a metabolic bypass to enhance mitochondrial respiration and maintain cell viability, which contributes to drug resistance in AML [51]. ...

Lactate Utilization Enables Metabolic Escape to Confer Resistance to BET Inhibition in Acute Myeloid Leukemia
  • Citing Article
  • January 2024

Cancer Research