About

Jeffrey Rathmell is a professor at the University of Chicago, holding the Jeffrey Rathmell Chair of the Ben May Department of Cancer Research, the Virginia and D. K. Ludwig Chair Professor for Cancer Research, and serving on multiple committees including Cancer Biology, Immunology, and Molecular Metabolism and Nutrition. His research focuses on how metabolic pathways and nutrient microenvironments regulate lymphocyte metabolism, differentiation, and function. His lab aims to understand the mechanisms of metabolic reprogramming during T lymphocyte activation, exploring how these processes influence immune cell fate and function within contexts such as obesity, cancer immunotherapy, and inflammatory microenvironments. Rathmell's work employs genetic and metabolic techniques to uncover how metabolic pathways impact immune responses, with particular interest in the effects of obesity on cancer treatment and the shaping of immune cell metabolism by inflammatory environments.

Research topics

• Biology
• Endocrinology
• Immunology
• Cell biology
• Genetics
• Chemistry
• Biochemistry
• Cancer research
• Biotechnology
• Neuroscience

Selected publications

• Ovarian hormones and obesity drive Th17-mediated airway inflammation through estrogen receptor-α signaling

  American Journal of Physiology-Lung Cellular and Molecular Physiology · 2026-02-13

  articleOpen access

  Estrogen receptor-alpha (ER-α) signaling increased obesity and allergen-induced airway inflammation in mice. In addition, women with obesity and asthma had increased circulating Th17 cells compared with men with obesity and asthma. These findings provide mechanistic insights into the intersection of obesity, sex hormones, and airway inflammation-underscoring the importance of personalized approaches to managing individuals with obesity and asthma.

  PublisherOA PDFDOI

• Acetyl-CoA Carboxylase-1 Inhibition Increases Regulatory T-cell Metabolism and Graft-Vs-Host Disease Treatment Efficacy Via Mitochondrial Fusion

  Transplantation and Cellular Therapy · 2026-02-01 · 1 citations

  article
  PublisherDOI

• Abstract A001: Mitochondrial potential as a biomarker of T cell fitness and function in cancer immunotherapy

  Cancer Research · 2026-03-13

  articleSenior author

  Abstract Checkpoint inhibitors have transformed cancer treatment, yet predicting responses remains challenging. Mitochondrial quality decreases in tumor infiltrating lymphocytes and correlates with impaired anti-tumor immunity in animal models. Mitochondrial membrane potential (MMP) increases with T cell activation but may also indicate cellular dysfunction. Here we assessed the MMP of tumor-associated T cells as an indicator of cell phenotypes and immunotherapy responses in Non-Small Cell Lung Carcinoma and clear cell Renal Cell Carcinoma patients. Primary tumors were collected followed by analysis of peripheral blood mononuclear cells (PBMC) prior to and after three weeks on treatment with immune checkpoint inhibition (ICI). PBMC T cells were analyzed for MMP using tetramethylrhodamine ethyl ester (TMRE) and sorted into high and low populations. TCRβ and single cell RNA sequencing of primary tumors identified and characterized peripheral blood T cell clones associated with the tumor microenvironment. As anticipated, ICI therapy increased the frequency of effector T cells in patients who experienced clinical benefit. TMREhigh peripheral blood T cells with tumor-matching TCRβ sequences had elevated oxidative phosphorylation gene signatures. Gene signatures of stress and exhaustion, such as Tigit and Cmc1, were also elevated in the TMREhigh CD8 T cell populations while gene expression patterns in TMRElow cells suggested mitochondrial fitness and cell longevity. Importantly, clinical benefit from ICI was negatively correlated with the TMREhigh CD8 T cell gene expression signature. These findings highlight a T cell population characterized by elevated MMP that correlates with exhaustion-like transcriptional states and poor response to immunotherapy. Citation Format: Katy Beckermann, Paul Lindau, Alex Nesta, Caroline Roe, Anupama Reddy, Kimryn Rathmell, Jonathan Irish, Jeffrey Rathmell. Mitochondrial potential as a biomarker of T cell fitness and function in cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A001.

  PublisherDOI

• Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis

  Nature Immunology · 2026-01-15 · 3 citations

  articleOpen accessSenior author

  Abstract Metabolic and immunologic dysfunction, including pathological CD4 + T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the 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 subset-specific metabolic plasticity, with regulatory T (T reg ) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted T reg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of T reg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in T reg cells. These findings indicate that metabolic dysfunction was a contributor to CD4 + T cell remodeling in critical illness and suggest avenues to restore effective immunity.

  PublisherDOI

• Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1

  Cell Metabolism · 2026-03-23

  articleOpen accessSenior authorCorresponding

  Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4 + T cell subset requirements for specific AAs remains uncertain. Here, we tested CD4 + T cell AA demands with in vitro and in vivo CRISPR screens and identified subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion in vivo in lung inflammation, SLC38A1 was critical for Th1, but not Th17, cell-driven experimental autoimmune encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing glutamine uptake and disrupting hexosamine biosynthesis and redox regulation. Pharmacological inhibition of SLC38 transporters also delayed Th1-mediated EAE but did not affect lung inflammation. CD4 + T cells thus have subset- and tissue-specific nutrient transporter dependencies that may guide new metabolic approaches for selective immunotherapies. • SLC38A1 contributes to glutamine uptake to aid Th1, but not Th17, cell proliferation • Th1 cell redox and hexosamine pathways selectively depend on SLC38A1 • SLC38A1 plays tissue-selective roles in gut and brain, but not lung, inflammation • T cell nutrient transporter needs vary based on subset, disease, and tissue site Metabolic demands and mechanisms of nutrient uptake shape T cell function and offer new therapeutic opportunities, but selective targeting remains challenging. Here, in vivo CRISPR screens show that CD4 T cell metabolism and nutrient uptake vary based on both cell subset and the tissue and inflammatory site.

  PublisherDOI

• Regulatory T cells rely on CD71 expression for metabolic stability in specific tissues 9360

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Regulatory T cells (Tregs) are a subset of CD4 T helper cells that combat autoimmune diseases. Treg function relies on a distinct cellular metabolism, distinguishing them from pro-inflammatory T cells. We showed that targeting the transferrin receptor for iron, CD71, depleted pro-inflammatory T cells while promoting Tregs and their Foxp3 expression. However, CD71-knockout (KO) in Tregs is lethal in mice. These mice develop spontaneous autoimmunity similar to scurfy mice, and show defective perinatal Treg expansion. Despite this phenotype, it is unclear whether KO Tregs retain any suppressive capacity or simply fail to proliferate. We tested the suppressive function of KO Tregs in a colitis model. CD71-KO Tregs significantly reduced disease pathology in the colon compared to mice that received no Tregs, although not as effectively as WT Tregs. Foxp3YFP-Cre-mediated deletion of CD71 in immunocompetent mice results in tissue-specific inflammation. The colon, kidney, and pancreas of mice with KO Tregs appeared healthy, whereas skin and lung tissue were severely inflamed. RNA-sequencing and flow cytometry analyses revealed that in affected tissues, KO Tregs are unstable, adopting T-bet and RORγt expression in addition to Foxp3. These KO Tregs also exhibit elevated Nrf2 signaling indicative of high oxidative stress and adopt a metabolism high in glycolysis. Thus, Tregs rely on CD71 for their stability and function at specific tissue sites such as the lung but not the colon. Funding Sources K.V. is supported by the Breakthrough T1D Advanced Postdoctoral Fellowship. Topic Categories Basic Autoimmunity (BA)

  PublisherOA PDFDOI

• Author response: Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling

  2025-08-18

  peer-reviewOpen access

  The efficiencies with which activated B lymphocytes proliferate and develop into antibody (Ab)- secreting plasma cells are critical determinants of adaptive humoral immunity and central to sustaining certain autoimmune diseases. Increasing evidence indicates that specific pathways in intermediary metabolism, or their substrate supply, influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases proliferation and differentiation of B cells into plasma cells, glutaminolysis - a major means of metabolism of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Strikingly, Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases only when either glucose uptake into B cells or pyruvate into their mitochondria was also impaired. This synthetic auxotrophy involved support to a progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel not only decreased the coupling of IL-21 stimulation to STAT3 induction, but also interferon stimulation of STAT1 activation. Together, our findings establish not only a powerful collaboration of metabolic pathways in promoting increased respiration and the development of Ab-secreting cells, but also a capacity of metabolism to modulate cytokine receptor signaling.

  PublisherDOI

• Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling

  eLife · 2025-08-18

  articleOpen access

  Abstract The efficiencies with which activated B lymphocytes proliferate and develop into antibody (Ab)- secreting plasma cells are critical determinants of adaptive humoral immunity and central to sustaining certain autoimmune diseases. Increasing evidence indicates that specific pathways in intermediary metabolism, or their substrate supply, influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases proliferation and differentiation of B cells into plasma cells, glutaminolysis - a major means of metabolism of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Strikingly, Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases only when either glucose uptake into B cells or pyruvate into their mitochondria was also impaired. This synthetic auxotrophy involved support to a progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel not only decreased the coupling of IL-21 stimulation to STAT3 induction, but also interferon stimulation of STAT1 activation. Together, our findings establish not only a powerful collaboration of metabolic pathways in promoting increased respiration and the development of Ab-secreting cells, but also a capacity of metabolism to modulate cytokine receptor signaling.

  PublisherDOI

• ATP citrate lyase (ACLY) regulates pro-inflammatory phenotypes in regulatory T cells in response to oxidized phospholipids 3848

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Regulatory T cells (Tregs) protect against atherosclerosis but lose stability and function as the disease progresses. Our lab has recently identified that the oxidized phospholipid oxPAPC (oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphocholine), enriched in atherosclerosis, induces a Th1-like, T-bet+ IFNγ+ phenotype during inducible Treg differentiation. These cells have reduced suppressive capacity in vitro and are less protective against atherosclerosis in vivo. However, the mechanism of oxPAPC-induced Treg dysfunction remains unknown. We sought to elucidate this mechanism and show that the oxPAPC-induced Th1-like phenotype depends on ATP citrate lyase (ACLY), which regulates the conversion of citrate to acetyl-CoA, a metabolite with important roles in the epigenetic regulation of IFNγ production. We found that supplementing cultures with exogenous acetate, which increases acetyl-CoA levels in an ACLY-independent manner, restores the Th1-like phenotype in Acly deficient cells differentiated with oxPAPC. This indicates ACLY may act as a link between oxPAPC and pro-inflammatory cytokine expression via acetyl-CoA regulation. A role for ACLY in murine atherosclerosis was examined using mice with T-cell specific ACLY knockout. CD4Cre+Aclyfl/fl mice had reductions in T-bet+ Tregs and increased plaque stability compared to CD4Cre-Aclyfl/fl mice, indicating a pro-atherogenic role for T-cell ACLY. Overall, our findings support a role for T-cell ACLY in atherosclerosis. Funding Sources Supported by T32AI138932; NIAID R01AI153167; NIH R21AI176219; VA Merit Grant I01BX002968 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

  PublisherOA PDFDOI

• 661 Retatrutide monotherapy matches the effectiveness of anti-PD-1 immunotherapy in a preclinical model of pancreatic cancer

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R21CA194829

  NIH · $376k · 2017

• Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease

  NIH · $4.7M · 2015–2027

• NIH Grant R03AI106835

  NIH · $157k · 2015

• NIH Grant R01AI063345

  NIH · $1.9M · 2012

• NIH Grant R56AI102074

  NIH · $393k · 2014

Frequent coauthors

• Jonathan L. Coloff

  Illinois College

  96 shared

• Craig B. Thompson

  90 shared

• W. Kimryn Rathmell

  89 shared

• David R. Plas

  University of Cincinnati

  72 shared

• Sarah R. Jacobs

  Albert Einstein College of Medicine

  71 shared

• Ryan D. Michalek

  56 shared

• Andrew N. Macintyre

  Duke University

  54 shared

• Nancie J. MacIver

  51 shared

Labs

• Jeffrey Rathmell LabPI

Education

• B.S., Biology

  University of Northern Iowa

  1991

• Ph.D., Immunology

  Stanford University

  1996

• Other, Cancer biology & metabolism

  University of Chicago

  1999

• Other, Cancer biology & metabolism

  University of Pennsylvania

  2003

Awards & honors

• Fred W. Alt Award for New Discoveries in Immunology (2025)
• Honorary Member American Society for Clinical Investigator (…
• Waddell Walker Hancock Cancer Discovery Scholar Vanderbilt U…
• Clarivate Highly Cited Researcher (2022 - 24)
• Nature Milestones: Highlighted for discoveries in T cell imm…