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Immune cells, such as T cells, play a critical role in establishing and maintaining whole organism health, while aberrant immune cell function underlies a host of diseases ranging from immunodeficiency to autoimmunity. As a model system for cellular differentiation, immune cells have the unique property of both maintaining homeostasis and responding to environmental or pathogenic insult.
Using NextGen sequencing technologies, Amanda Poholek, PhD, and her team of researchers are seeking to understand how tissue-specific environments control T cell differentiation and function at the transcriptomic and epigenomic level to understand the greater impact of immune cell regulation on health and disease.
Transcription factors play a critical role in modulating the transcriptome and epigenome of cells. Blimp-1 is a BTB/POZ zinc finger transcription factor expressed by many cell types, including T and B cells. In T cells, we have identified context-dependent functions of Blimp-1 controlling T cell differentiation and effector function and are exploring the molecular regulation and function of Blimp-1 as a model transcription factor that controls immune cells in health in disease. Our research on Blimp-1 seeks to answer the following questions:
Our studies have uncovered novel genomic elements controlling the expression of Blimp-1 and the tissue-specific functions of Blimp-1 that control autoimmunity while also promoting responses to allergens. Using genetic mouse models and NextGen sequencing technologies, we are, at the molecular level, exploring how this important transcription factor shapes T cell differentiation and function at homeostasis and in the face of contextual environmental changes.
Blimp-1 promotes Th2 cells in allergic asthma (Created with BioRender.com)
In collaboration with Greg Delgoffe, PhD, at the UPMC Hillman Cancer Center, we are exploring the epigenetics of T cells in murine tumors using a new low-cell number ChIP-seq assay (CUT & RUN) developed by Steven Henikoff, PhD, at the Fred Hutchinson Cancer Research Center. As T cells enter a tumor’s micro-environment, they experience a unique combination of signals that promote a state of T cell dysfunction (also called exhaustion). Our lab is working to understand the transcriptomic and epigenomic landscape of T cell exhaustion in a tumor in order to understand the signals that drive exhaustion and identify novel therapeutic targets for immunotherapy.
Profiling the epigenome of T cell exhaustion
T cells are unique in that they can rapidly shift their metabolism after activation as well as undergo rapid cell division. The cellular mechanics that underlie these changes are unique to T cells and are in the early stages of being understood. Our lab is using NextGen sequencing technologies to modulate the environmental signals and metabolic requirements that T cells experience after activation to determine the intersection of these inputs on the epigenetic landscape. Our goal is to understand how shifts in metabolites or environmental signals impact T cell differentiation and function from the initiation of T cell activation at the chromatin level so as to understand the plasticity and heterogeneity that exists in the T cell compartment in vivo.
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PMI Graduate Student
Kun He, PhD
Tsinghua Scholar – Tsinghua University School of Medicine
Undergraduate Student – Molecular Biology
The Poholek Lab
UPMC Children’s Hospital of Pittsburgh
John G. Rangos Sr. Research Center, Suite 8129
4401 Penn Avenue
Pittsburgh, PA 15224
View current news featuring the research, staff and advancements of the Poholek Lab for Molecular Immune Cell Research at UPMC Children’s Hospital of Pittsburgh’s Richard King Mellon Institute for Pediatric Research. Please check back often for continued updates.
The Poholek Lab received the Catalytic Award from the Pittsburgh Autoimmunity Center of Excellence in Rheumatology for studies on the metabolic regulation of epigenetic dysfunction in CD4 T cells in lupus, a new area of research in the lab exploring the intersections of metabolism and epigenetics in lupus patient samples.
The Lab’s study on Blimp-1 in allergic asthma was highlighted by the Journal of Allergy and Clinical Immunology in its online component, News Beyond Our Pages.
The Poholek Lab received a Pilot Grant Award from the Richard King Mellon Institute for Pediatric Research for studies on the role of Blimp-1 in allergen-driven ILC2s, an extension of our research on the context-dependent regulation and function of Blimp-1 in the immune system.
The Blueprint for Everything, a podcast featuring Amanda Poholek, PhD, was added to the “That’s Pediatrics” series.
2019 Apr 9
Amanda Poholek, PhD, presented the lab’s work on Blimp-1 in allergic asthma at the Virtual Keystone Symposia, Asthma: New Discoveries and Therapies in the Age of COVID.
Kun He, PhD, presented his work on Blimp-1 in Th2 cell development in the lung at the International Cytokine & Interferon Society’s Cytokines 2020 virtual meeting.
Amanda Poholek, PhD, presented “Allergen-induced airway inflammation and Th2 cell development requires Blimp-1” at the American Association for Immunologists meeting in San Diego.
Kun He, PhD, received the Milstein Abstract Award for his submission to the International Cytokine & Interferon Society’s Cytokines 2020.
UPMC Hillman Cancer Center Academy student Noelle Hutchinson concluded her summer in the lab with the poster presentation, “Comparison of light microscopy and flow cytrometry quantification of differential leukocytes in bronchoalveolar lavage fluid of asthmatic lungs.”
Blimp-1 is Essential for Allergen-induced Asthma and Th2 Cell Development in the Lung
He K, Hettinga A, Kale SL, Hu S, Xie MM, Dent AL, Ray A, Poholek AC
The Journal of Experimental Medicine
2020 May 12
IL-10 Induces a STAT3-dependent Autoregulatory Loop in Th2 Cells That Promotes Blimp-1 Restriction of Cell Expansion via Antagonism of STAT5 Target Genes
Poholek AC, Jankovic D, Villarino AV, Petermann F, Hettinga A, Shouval DS, Snapper SB, Kaech SM, Brooks SR, Vahedi G, Sher A, Kanno Y, O'Shea JJ
2016 Nov 11
Transcriptional and Epigenetic Networks of Helper T Cells and Innate Lymphoid Cells
Shih HY, Sciume G, Poholek AC, Vahedi G, Hirahara K, Villarino A, Bonelli M, Bosselut R, Kanno Y, Muljo S, O’Shea JJ
2014 Aug 14
Type I Interferon Induces Binding of STAT1 to Bcl6: Divergent Roles of STAT-family transcription factors in the TFH Cell Genetic Program
Nakayamada S*, Poholek AC*, Lu KT, Takahashi H, Hirahara K, Kato, M, Iwata S, Cannons JL, Schwartzberg PL, Vahedi G, Sun H, Kanno Y, O’Shea JJ
The Journal of Immunology
2014 Mar 1
Helper T Cell Identity and Evolution of Differential Transcriptomes and Epigenomes
Vahedi G*, Poholek AC*, Hand TW, Laurence A, Kanno Y, O’Shea JJ, Hirahara K
2013 Feb 13
In Vivo Regulation of Bcl6 and T Follicular Helper Cell Development
Poholek AC, Hansen K, Hernandez S, Eto D, Chandele A, Weinstein JS, Dong X, Odegard J, Kaech SM, Dent AL, Crotty S, Craft J
The Journal of Immunology
2010 Jul 1
Bcl6 and Blimp-1 are Reciprocal and Antagonist Regulators of T Follicular Helper Cell Differentiation
Johnston R*, Poholek AC*, DiToro D, Yusuf I, Eto D, Barnett B, Dent A, Craft J, Crotty S
2009 Aug 2
The Poholek Lab is looking for talented post-doctoral fellows and graduate students interested in our areas of investigation. Please inquire to Dr. Poholek via email.
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