Maria Ciofani

Overview:


Transcriptional Regulation of Proinflammatory Lymphocytes

IL-17-expressing CD4 T helper (Th17) cells are important members of the intestinal immune cell community that contribute to protection against bacterial and fungal infections, and maintenance of intestinal homeostasis.  Although central to immunity, dysregulted Th17 cell function has been implicated in tissue inflammation and autoimmune disease (e.g. Inflammatory bowel disease, arthritis, and multiple sclerosis).  In order to understand this balance between healthy and pathogenic responses, we are interested in defining the transcriptional regulatory mechanisms that govern (1) Th17 cell specification from naive T cell precursors and, (2) Th17 cell effector plasticity during inflammation.  Combining genome-wide interrogation of regulatory information (transcription factor occupancy, chromatin accessibility, and transcriptional output) with gene-deficiency models in mice, we can dissect the contribution of key transcriptional regulators in proinflammatory T cell function.



We currently have open positions for students, postdoctoral fellows and a research technician.


Positions:

Associate Professor of Immunology

Immunology
School of Medicine

Associate Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

University of Toronto (Canada)

Grants:

The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Network approach to dissecting genetic mediators of Multiple Sclerosis

Administered By
Immunology
Awarded By
National Multiple Sclerosis Society
Role
Principal Investigator
Start Date
End Date

The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Regulatory mechanisms governing Th17 cell effector identity and plasticity

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Transgenic mice for in vivo epigenome editing with CRISPR-based systems.

CRISPR-Cas9 technologies have dramatically increased the ease of targeting DNA sequences in the genomes of living systems. The fusion of chromatin-modifying domains to nuclease-deactivated Cas9 (dCas9) has enabled targeted epigenome editing in both cultured cells and animal models. However, delivering large dCas9 fusion proteins to target cells and tissues is an obstacle to the widespread adoption of these tools for in vivo studies. Here, we describe the generation and characterization of two conditional transgenic mouse lines for epigenome editing, Rosa26:LSL-dCas9-p300 for gene activation and Rosa26:LSL-dCas9-KRAB for gene repression. By targeting the guide RNAs to transcriptional start sites or distal enhancer elements, we demonstrate regulation of target genes and corresponding changes to epigenetic states and downstream phenotypes in the brain and liver in vivo, and in T cells and fibroblasts ex vivo. These mouse lines are convenient and valuable tools for facile, temporally controlled, and tissue-restricted epigenome editing and manipulation of gene expression in vivo.
Authors
Gemberling, MP; Siklenka, K; Rodriguez, E; Tonn-Eisinger, KR; Barrera, A; Liu, F; Kantor, A; Li, L; Cigliola, V; Hazlett, MF; Williams, CA; Bartelt, LC; Madigan, VJ; Bodle, JC; Daniels, H; Rouse, DC; Hilton, IB; Asokan, A; Ciofani, M; Poss, KD; Reddy, TE; West, AE; Gersbach, CA
MLA Citation
Gemberling, Matthew P., et al. “Transgenic mice for in vivo epigenome editing with CRISPR-based systems.Nat Methods, vol. 18, no. 8, Aug. 2021, pp. 965–74. Pubmed, doi:10.1038/s41592-021-01207-2.
URI
https://scholars.duke.edu/individual/pub1492755
PMID
34341582
Source
pubmed
Published In
Nat Methods
Volume
18
Published Date
Start Page
965
End Page
974
DOI
10.1038/s41592-021-01207-2

Regulation of γδ T Cell Effector Diversification in the Thymus.

γδ T cells are the first T cell lineage to develop in the thymus and take up residence in a wide variety of tissues where they can provide fast, innate-like sources of effector cytokines for barrier defense. In contrast to conventional αβ T cells that egress the thymus as naïve cells, γδ T cells can be programmed for effector function during development in the thymus. Understanding the molecular mechanisms that determine γδ T cell effector fate is of great interest due to the wide-spread tissue distribution of γδ T cells and their roles in pathogen clearance, immunosurveillance, cancer, and autoimmune diseases. In this review, we will integrate the current understanding of the role of the T cell receptor, environmental signals, and transcription factor networks in controlling mouse innate-like γδ T cell effector commitment.
Authors
Parker, ME; Ciofani, M
MLA Citation
Parker, Morgan E., and Maria Ciofani. “Regulation of γδ T Cell Effector Diversification in the Thymus.Front Immunol, vol. 11, 2020, p. 42. Pubmed, doi:10.3389/fimmu.2020.00042.
URI
https://scholars.duke.edu/individual/pub1431095
PMID
32038664
Source
pubmed
Published In
Frontiers in Immunology
Volume
11
Published Date
Start Page
42
DOI
10.3389/fimmu.2020.00042

Functional heterogeneity of alveolar macrophage population based on expression of CXCL2.

Alveolar macrophages (AMs) are the major lung-resident macrophages and have contradictory functions. AMs maintain tolerance and tissue homeostasis, but they also initiate strong inflammatory responses. However, such opposing roles within the AM population were not known to be simultaneously generated and coexist. Here, we uncovered heterogeneous AM subpopulations generated in response to two distinct pulmonary fungal infections, Cryptococcus neoformans and Aspergillus fumigatus Some AMs are bona fide sentinel cells that produce chemoattractant CXCL2, which also serves as a marker for AM heterogeneity, in the context of pulmonary fungal infections. However, other AMs do not produce CXCL2 and other pro-inflammatory molecules. Instead, they highly produce anti-inflammatory molecules, including interleukin-10 (IL-10) and complement component 1q (C1q). These two AM subpopulations have distinct metabolic profiles and phagocytic capacities. We report that polarization of pro-inflammatory and anti-inflammatory AM subpopulations is regulated at both epigenetic and transcriptional levels and that these AM subpopulations are generally highly plastic. Our studies have uncovered the role of C1q expression in programming and sustaining anti-inflammatory AMs. Our finding of the AM heterogeneity upon fungal infections suggests a possible pharmacological intervention target to treat fungal infections by tipping the balance of AM subpopulations.
Authors
Xu-Vanpala, S; Deerhake, ME; Wheaton, JD; Parker, ME; Juvvadi, PR; MacIver, N; Ciofani, M; Shinohara, ML
MLA Citation
Xu-Vanpala, Shengjie, et al. “Functional heterogeneity of alveolar macrophage population based on expression of CXCL2.Science Immunology, vol. 5, no. 50, Aug. 2020. Epmc, doi:10.1126/sciimmunol.aba7350.
URI
https://scholars.duke.edu/individual/pub1453708
PMID
32769172
Source
epmc
Published In
Science Immunology
Volume
5
Published Date
DOI
10.1126/sciimmunol.aba7350

In Vitro Differentiation of CD4+ T Cell Effector and Regulatory Subsets.

In vitro differentiation of naïve CD4+ T cells into effector and regulatory subsets offers a means to acquire large numbers of relatively homogeneous cell populations for experimentation. However, culture systems for T cell differentiation described in the literature vary widely in efficiency and complexity, limiting their comparison across studies. Here, we present a standardized and robust method for the isolation and in vitro differentiation of six CD4+ T cell subsets from mouse naïve T cells.
Authors
Espinosa, JR; Wheaton, JD; Ciofani, M
MLA Citation
Espinosa, Jaclyn R., et al. “In Vitro Differentiation of CD4+ T Cell Effector and Regulatory Subsets.Methods Mol Biol, vol. 2111, 2020, pp. 79–89. Pubmed, doi:10.1007/978-1-0716-0266-9_7.
URI
https://scholars.duke.edu/individual/pub1428654
PMID
31933200
Source
pubmed
Published In
Methods Mol Biol
Volume
2111
Published Date
Start Page
79
End Page
89
DOI
10.1007/978-1-0716-0266-9_7

JunB Controls Intestinal Effector Programs in Regulatory T Cells.

Foxp3-expressing regulatory T (Treg) cells are critical mediators of immunological tolerance to both self and microbial antigens. Tregs activate context-dependent transcriptional programs to adapt effector function to specific tissues; however, the factors controlling tissue-specific gene expression in Tregs remain unclear. Here, we find that the AP-1 transcription factor JunB regulates the intestinal adaptation of Tregs by controlling select gene expression programs in multiple Treg subsets. Treg-specific ablation of JunB results in immune dysregulation characterized by enhanced colonic T helper cell accumulation and cytokine production. However, in contrast to its classical binding-partner BATF, JunB is dispensable for maintenance of effector Tregs as well as most specialized Treg subsets. In the Peyer's patches, JunB activates a transcriptional program facilitating the maintenance of CD25- Tregs, leading to the complete loss of T follicular regulatory cells in the absence of JunB. This defect is compounded by loss of a separate effector program found in both major colonic Treg subsets that includes the cytolytic effector molecule granzyme B. Therefore, JunB is an essential regulator of intestinal Treg effector function through pleiotropic effects on gene expression.
Authors
Wheaton, JD; Ciofani, M
MLA Citation
Wheaton, Joshua D., and Maria Ciofani. “JunB Controls Intestinal Effector Programs in Regulatory T Cells.Front Immunol, vol. 11, 2020, p. 444. Pubmed, doi:10.3389/fimmu.2020.00444.
URI
https://scholars.duke.edu/individual/pub1438511
PMID
32296416
Source
pubmed
Published In
Frontiers in Immunology
Volume
11
Published Date
Start Page
444
DOI
10.3389/fimmu.2020.00444

Research Areas:

Animals
Antigens, CD4
Autoimmune Diseases
Autoimmunity
Basic-Leucine Zipper Transcription Factors
Bone Marrow Cells
CD4 Antigens
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Aging
Cell Cycle
Cell Death
Cell Differentiation
Cell Division
Cell Line
Cell Lineage
Cell Survival
Cells, Cultured
Chromatin Immunoprecipitation
Cloning, Molecular
Coculture Techniques
Cytokines
Cytotoxicity Tests, Immunologic
DEAD-box RNA Helicases
DNA Mutational Analysis
DNA-Binding Proteins
Developmental Biology
Disease Models, Animal
Drosophila
Drosophila Proteins
Early Growth Response Protein 1
Encephalomyelitis, Autoimmune, Experimental
Enhancer Elements, Genetic
Enzyme Activation
Epigenesis, Genetic
Epitopes
Extracellular Signal-Regulated MAP Kinases
Female
Fetus
Flow Cytometry
Fluorescent Antibody Technique
Fos-Related Antigen-2
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Leukemic
Gene Library
Gene Rearrangement
Gene Regulatory Networks
Genome-Wide Association Study
Hematopoietic Stem Cells
Hepatocytes
Humans
Immunomodulation
Inhibitor of Apoptosis Proteins
Inhibitor of Differentiation Proteins
Interferon Regulatory Factors
Intracellular Signaling Peptides and Proteins
Kinetics
Leukemia, T-Cell
Ligands
Lymphocyte Activation
Lymphoid Progenitor Cells
Lymphopoiesis
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Mice, Transgenic
MicroRNAs
Microtubule-Associated Proteins
Models, Genetic
Molecular Sequence Data
Mutation
Neoplasm Proteins
Nuclear Receptor Subfamily 1, Group F, Member 3
Organ Culture Techniques
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Phosphorylation
Pregnancy
Protein Isoforms
Protein Precursors
Proto-Oncogene Proteins c-akt
RGS Proteins
RNA Precursors
RNA Processing, Post-Transcriptional
Receptor, Notch1
Receptors, Antigen, T-Cell
Receptors, Antigen, T-Cell, alpha-beta
Receptors, Antigen, T-Cell, gamma-delta
Receptors, Notch
Regulatory Elements, Transcriptional
Reverse Transcriptase Polymerase Chain Reaction
Ribonuclease III
Sequence Analysis, RNA
Signal Transduction
Stem Cells
Stromal Cells
Systems Biology
T-Lymphocyte Subsets
T-Lymphocytes
T-Lymphocytes, Helper-Inducer
Th17 Cells
Thymus Gland
Transcription Factor AP-1
Transcription Factors
Transcription, Genetic
Transcriptional Activation
Transgenes
Tumor Suppressor Protein p53