Overview

Cytokines are critical for host defense but are also key factors in immune and inflammatory diseases. Innate and adaptive lymphocytes, including T cells, are important selective producers of cytokines, and it is through the production of these that immune responses work together to eliminate microbial pathogens. Host defense against pathogenic microorganisms requires this elegant means of communication between innate and adaptive arms of the immune system. Indeed, cytokines produced by various types of lymphocytes exquisitely tailor immune responses that effectively eliminate intracellular and extracellular pathogens when regulated properly. On the other hand, hyper-active lymphocytes can drive allergic and autoimmune diseases. Conversely, loss-of-function mutations of lymphocyte genes can cause primary immunodeficiencies.

The goal of the Molecular Immunology and Inflammation Branch (MIIB) is to understand how lymphocytes differentiate to selectively produce key immunoregulatory cytokines and to better define the molecular basis of cytokine action.

Discovery of JAK3 and Development of Jakinibs

We now know that a plethora of cytokines is produced by innate immune cells and that these cytokines are critical for the development and specification of CD4 subsets. A substantial portion of cytokines (more than 60) binds to receptors that associate with a class of protein tyrosine kinases termed Janus Kinases or JAKs (illustrated in Figure 2). The MIIB first cloned human JAK3, a kinase predominantly expressed in immune and hematopoietic cells; in partnership with NIH colleagues, the branch went on to demonstrate that JAK3 associates with the common γ chain (γc). This shared cytokine receptor is used by interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21, and we found that mutations of JAK3 underlie autosomal recessive severe combined immunodeficiency (SCID). Because of the critical functions of JAKs in cytokine signaling, pharmacological JAK inhibitors (jakinibs) were developed as a new class of immunomodulatory drugs. The NIH holds patents pertaining to Janus Kinases and identification of immune modulators (United States patents 7,070,972 and 7,488,808). The NIAMS partnered with Pfizer in a Cooperative Research and Development Agreement (CRADA), leading to the development of multiple jakinibs. At present, there are nine approved jakinibs for indications ranging from rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, ulcerative colitis, atopic dermatitis, graft-vs-host disease, and myeloproliferative neoplasms to COVID-19. The MIIB, in collaboration with other investigators, is studying the efficacy of jakinibs in lupus, Sjogren’s syndrome, and other disorders.

Helper T cell differentiation (O'Shea and Paul. 2010.
Figure 1 - Targeting JAKs in human diseases by Jakinibs (Spinelli FR et al. Eur J Immunol 2021. PubMed: 33930196)

Cytokine Signaling via STATs

Image
JAK-STAT Pathway
Figure 2 - JAK-STAT pathway (Gadina et al. Rheumatology (Oxford). 2019.  PubMed: 30806710)

STAT4

The MIIB demonstrated that IL-12 activates STAT4, a key factor that initiates the development of Th1 cells that produce the signature cytokine interferon-γ (IFN-γ). The branch has continued its interest in dissecting the function of STAT4 over the last 16 years since this initial discovery. Most recently, we have used second-generation, deep sequencing technology to define the genome-wide targets of STAT4 and relate this knowledge to the roles of STAT4 in regulating gene expression and changes in the epigenome of differentiating CD4+ T cells. Capitalizing on the opportunities provided by deep sequencing technology and computational biology tools, defining the genome-wide functions of STAT4 and other STATs is a focal point of research in the lab.

STAT3

Th17 cell differentiation is dependent upon this transcription factor. Importantly, the Job's syndrome or Hyper IgE syndrome (HIES) disorder is due to mutations of STAT3. The MIIB, in collaboration with other NIH scientists, showed that a major defect in this disorder is impairment of Th17 cell generation. We used Chip-seq methodology to identify STAT3 target genes in developing Th17 cells. Dissecting the functions of STAT3 in this intriguing subset of cells is an ongoing interest of the lab.

Helper T cell differentiation (O'Shea and Paul. 2010.
Figure 3 - Helper T cell differentiation (O'Shea et al. Science 2010. PubMed: 20185720)

STAT1

Patients with STAT1 gain-of-function mutations have clinical presentations similar in many respects to patients with HIES. We are currently studying mouse models to increase our understanding of the pathophysiology of the rare Mendelian disease, which may provide insights into more common diseases.

STAT5

In addition to Th cells, regulatory T (Treg) cells represent another important immunoregulatory subset of CD4+ T cells. The MIIB showed that STAT5 is critical for Treg cell differentiation, binding to the gene encoding the transcription factor Foxp3. Conversely, we showed that STAT5, in response to IL-2 stimulation, also inhibits Th17 differentiation. We further showed STAT5 and STAT3 compete in the Il7a-Il17f locus and that this is an important mechanism underlying the ability of IL-2 to limit Th17 differentiation.

Latest Research into Transcriptome and Epigenome

Image
Flexibility in lymphocyte epigenomes
Figure 4 - Flexibility in lymphocyte epigenomes (Sciumè et al. Immunity 2020. PubMed: 33010223)

A major ongoing issue in lymphocyte biology is the extent to which different subsets behave as terminally differentiated lineages or retain flexibility in their differentiation programs. By assessing the epigenomes of the different helper cell subsets, we have identified mechanisms through which flexibility is retained, even in polarized "lineages." We have explored the issue of plasticity and heterogeneity of helper T cells and their relationship to innate lymphocytes. We have also explored in detail the structure of key cytokine loci including the Ifng/Il22 and Il4/Il13/Il5 super-enhancer loci.

Furthermore, we study how long noncoding RNAs and microRNAs regulate immune responses, how activation globally impacts chromatin accessibility and architecture, and how these concepts relate to lymphocyte function.

Future Directions

By studying how the engagement of cytokine receptors transduces signals that, in turn, regulate transcription factors and epigenetic events to modulate gene expression, we hope to understand in detail how lymphocytes participate in host defense and contribute to the pathogenesis of immune-mediated diseases. The insights gained from these studies facilitate the development of new therapeutic approaches.

Contact Us

Iris Pratt

Staff Assistant
9000 Rockville Pike
Building: 10, Room: 13C103
Bethesda MD 20892

Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:

Staff

Former Lab Members

U.S. Based

Adewole Adamson,
Assistant Professor, Dept. of Internal Medicine, The University of Texas at Austin, Austin, TX
Behdad Afzali,
Stadtman Tenure-Track Investigator, Kidney Diseases Section, NIDDK
Jay Bream,
Associate Professor, W. Harry Feinstone Dept. of Molecular Microbiology & Immunology, Johns Hopkins University, Baltimore, MD
Scott Canna,
Assistant Professor of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
Min Chen,
Associate Professor, Dept. of Pathology and Immunology, Baylor College of Medicine, Houston, TX
Alan Cheng,
Vice President, Medtronic; Associate Professor, Johns Hopkins University, Baltimore, MD
Tammy Cheng,
Rheumatologist, Ventura, CA
Donald Eicher,
Medical Oncologist, Cleveland Clinic, Cleveland, OH
Kevin Elias,
Director, Gynecologic Oncology Laboratory, Brigham and Women's Hospital; Assistant Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA
David Frucht,
Director, Division of Biotechnology Review and Research II, FDA
Massimo Gadina,
Director, Office of Science and Technology, NIAMS; Investigator, Translational Immunology Section, NIAMS
Eric Hansen,
Division Chief, Pediatric Rheumatology, Associate Professor of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
Bruce Hissong,
Patent Examiner, U.S. Patent and Trademark Office
Vance Holt,
Postdoctoral Fellow, NIAMS
Matthew Husa,
Rheumatologist, Denver, CO
James Johnston,
CSO/COO, ImmPACT-Bio USA Inc. Camarillo, CA 
Apostolos Kontzias,
Associate Professor, Dept. of Medicine; Vice Director, Center for Autoinflammatory Diseases, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY
Alex Kotlyar, Resident,
OB-GYN, Cleveland Clinic, Cleveland, OH
Brajesh Lal,
Professor of Surgery, Director of Vascular Surgery, University of Maryland, Baltimore, MD
Albert Lam,
Research/Clinical Fellow, Brigham and Women's Hospital; Assistant Professor of Medicine, Harvard Medical School, Boston, MA
Denise Li Lue,
Medical Director, Inpatient Rehabilitation Unit; Clinical Assistant Professor, Rehabilitation Medicine, University of Washington Medical Center, Seattle, WA
Daniel McVicar,
Deputy Scientific Director, Acting Chief, Laboratory of Cancer Immunometabolism, NCI
Scott Oakes,
Professor, Dept. of Pathology, University of California San Francisco, San Francisco, CA
Robert Ortmann,
Executive Director of Clinical Development, Horizon, Gaithersburg, MD 
Heiyoung Park,
Program Director, Scleroderma, Fibrosis, and Autoinflammatory Disease Program, NIAMS
Amanda Poholek,
Assistant Professor, Dept. of Immunology and Pediatrics, University of Pittsburgh, Pittsburgh, PA
Han-Yu Shih,
Investigator, NEI
Daniella Schwartz,
Assistant Clinical Investigator, NIAID
Kentner Singleton,
Program Officer, NIAID
Benjamin Solomon,
Medical Scientist Training Program, Washington University, Resident in Pathology, Stanford University, Stanford, CA
J. Erin Staples,
Investigator, Arboviral Diseases Section, CDC
Scott Stewart-Tharp,
Postdoctoral Research Fellow, Dept. of Pathology, University of Iowa, Iowa City, IA
Chitra Sudarshan,
Principal Scientist, MilliporeSigma, Rockville, MD
Cristina Tato,
Director, Rapid Response Team, Chan-Zuckerberg Biohub, San Francisco, CA
P. Justin Tortolani,
Spinal Surgeon, UM St. Joseph Medical Center, Towson, MD
Jacob Turner,
Scientist, HiFIBiO Therapeutics, Cambridge, MA
Kevin Urdahl,
Professor, Pediatrics, Seattle Children’s Research Institute, Adjunct Professor, Immunology, University of Washington, Seattle, WA
Golnaz Vahedi,
Associate Professor of Genetics, Penn Institute of Immunology, University of Pennsylvania, Philadelphia, PA
Wendy Watford,
Associate Professor, Dept. of Infectious Disease, University of Georgia, Athens, GA
Steven Witte,
Resident, University of Rochester Medical Center, Rochester, NY
Chen Yao,
Assistant Professor, University of Texas Southwestern Medical Center, Dallas, TX
Yongjie Zhou,
Physician Scientist, FDA

International

Davide Agnello,
Assistant Professor, University of Bourgogne, Dijon, France
Martin Aringer,
Professor, Director of Rheumatology, University of Dresden, Dresden, Germany
Christopher Bacon,
Senior Lecturer, Consultant Hematopathologist, Newcastle University, Newcastle upon Tyne, UK
Michael Bonelli,
Associate Professor, Division of Rheumatology, Medical University of Vienna, Austria
Fabio Candotti,
Associate Professor of Medicine, Head Physician, Division of Immunology and Allergy; Director, Vaccine and Immunotherapy Center, University Hospital of Lausanne, Lausanne, Switzerland
Zhi Chen,
Associate Professor, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Lydia Durant,
Teaching Fellow, Faculty of Medicine, Imperial College London, London, UK
Denis Franchimont,
Professor, Dept. of Gastroenterology, Braine-l'Alleud - Waterloo Hospital, Waterloo, Belgium
Jerome Galon,
Research Director, Head, Laboratory of Integrative Cancer Immunology, INSERM, Paris, France
Kamran Ghoreschi,
Director, Dept. of Dermatology, Venerology and Allergology, Charité Medical University of Berlin, Berlin, Germany
Kiyoshi Hirahara,
Associate Professor, Dept. of Immunology, Chiba University, Chiba, Japan
Sigrun Hofmann,
Dept. of Pediatrics, University of Dresden, Dresden, Germany
Shigeru Iwata,
Assistant Professor of Rheumatology, University of Occupational and Environmental Health, Fukuoka, Japan
Ian Kennedy,
Specialist, Dept. of Oncology, Waikato Hospital, Hamilton, New Zealand
Arian Laurence,
Blood and Marrow Transplant Consultant, University College London, London, UK
Lisa Mielke,
Head, Mucosal Immunology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
Yohei Mikami,
Associate Professor, Dept. of Internal Medicine, Keio University, Tokyo, Japan
Akio Morinobu,
Professor and Chair, Dept. of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan
Shingo Nakayamada,
Assistant Professor, The First Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
Marko Pesu,
Professor, Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
Giuseppe Sciume,
Associate Professor, Sapienza University of Rome, Rome, Italy
Hayato Takahashi,
Associate Professor, Dept. of Dermatology, Keio University, Tokyo, Japan
Hiroaki Takatori,
Director, Dept. of Rheumatology, Hamamatsu Medical Center, Shizuoka, Japan
Roberta Visconti,
Researcher, Italian National Research Council, Rome, Italy
Lai Wei,
Scientific Founder, Smilebiotek; Professor, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
Kunihiro Yamaoka,
Professor and Chair, Dept. of Rheumatology and Infectious Disease, Kitasato University, Tokyo, Japan
Xianping Yang,
Professor of Immunology, Tongji Medical University, Huazhong University of Science and Technology, Wuhan, China

Image & Media Gallery

Scientific Publications

Selected Recent Publications

The JAK-STAT pathway at 30: Much learned, much more to do.

Philips RL, Wang Y, Cheon H, Kanno Y, Gadina M, Sartorelli V, Horvath CM, Darnell JE Jr, Stark GR, O'Shea JJ
Cell.
2022 Oct 13;
185(21).
doi: 10.1016/j.cell.2022.09.023
PMID: 36240739

MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23.

Mikami Y, Philips RL, Sciumè G, Petermann F, Meylan F, Nagashima H, Yao C, Davis FP, Brooks SR, Sun HW, Takahashi H, Poholek AC, Shih HY, Afzali B, Muljo SA, Hafner M, Kanno Y, O'Shea JJ
Immunity.
2021 Mar 9;
54(3).
doi: 10.1016/j.immuni.2021.02.015
PMID: 33657395

Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells.

Sciumè G, Mikami Y, Jankovic D, Nagashima H, Villarino AV, Morrison T, Yao C, Signorella S, Sun HW, Brooks SR, Fang D, Sartorelli V, Nakayamada S, Hirahara K, Zitti B, Davis FP, Kanno Y, O'Shea JJ, Shih HY
Immunity.
2020 Oct 13;
53(4).
doi: 10.1016/j.immuni.2020.09.008
PMID: 33010223

Translating JAKs to Jakinibs.

Gadina M, Chisolm DA, Philips RL, McInness IB, Changelian PS, O'Shea JJ
J Immunol.
2020 Apr 15;
204(8).
doi: 10.4049/jimmunol.1901477
PMID: 32253269

The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

Petermann F, Pękowska A, Johnson CA, Jankovic D, Shih HY, Jiang K, Hudson WH, Brooks SR, Sun HW, Villarino AV, Yao C, Singleton K, Akondy RS, Kanno Y, Sher A, Casellas R, Ahmed R, O'Shea JJ
Mol Cell.
2019 Sep 19;
75(6).
doi: 10.1016/j.molcel.2019.06.025
PMID: 31377117

Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation.

Nagashima H, Mahlakõiv T, Shih HY, Davis FP, Meylan F, Huang Y, Harrison OJ, Yao C, Mikami Y, Urban JF Jr, Caron KM, Belkaid Y, Kanno Y, Artis D, O'Shea JJ
Immunity.
2019 Oct 15;
51(4).
doi: 10.1016/j.immuni.2019.06.009
PMID: 31353223

Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection.

Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, Heuston EF, Kirby M, Anderson S, Cheng J, Khan O, Handon R, Reilley J, Fioravanti J, Hu J, Gossa S, Wherry EJ, Gattinoni L, McGavern DB, O'Shea JJ, Schwartzberg PL, Wu T
Nat Immunol.
2019 Jul;
20(7).
doi: 10.1038/s41590-019-0403-4
PMID: 31209400

Janus kinases to jakinibs: from basic insights to clinical practice.

Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, O'Shea JJ
Rheumatology (Oxford).
2019 Feb 1;
58(Suppl 1).
doi: 10.1093/rheumatology/key432
PMID: 30806710

Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology.

Schwartz DM, Farley TK, Richoz N, Yao C, Shih HY, Petermann F, Zhang Y, Sun HW, Hayes E, Mikami Y, Jiang K, Davis FP, Kanno Y, Milner JD, Siegel R, Laurence A, Meylan F, O'Shea JJ
Immunity.
2019 Jan 15;
50(1).
doi: 10.1016/j.immuni.2018.12.014
PMID: 30650370

Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury.

Harrison OJ, Linehan JL, Shih HY, Bouladoux N, Han SJ, Smelkinson M, Sen SK, Byrd AL, Enamorado M, Yao C, Tamoutounour S, Van Laethem F, Hurabielle C, Collins N, Paun A, Salcedo R, O'Shea JJ, Belkaid Y
Science.
2019 Jan 4;
363(6422).
doi: 10.1126/science.aat6280
PMID: 30523076

The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells.

Iwata S, Mikami Y, Sun HW, Brooks SR, Jankovic D, Hirahara K, Onodera A, Shih HY, Kawabe T, Jiang K, Nakayama T, Sher A, O'Shea JJ, Davis FP, Kanno Y
Immunity.
2017 Jun 20;
46(6).
doi: 10.1016/j.immuni.2017.05.005
PMID: 28623086

BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

Afzali B, Grönholm J, Vandrovcova J, O'Brien C, Sun HW, Vanderleyden I, Davis FP, Khoder A, Zhang Y, Hegazy AN, Villarino AV, Palmer IW, Kaufman J, Watts NR, Kazemian M, Kamenyeva O, Keith J, Sayed A, Kasperaviciute D, Mueller M, Hughes JD, Fuss IJ, Sadiyah MF, Montgomery-Recht K, McElwee J, Restifo NP, Strober W, Linterman MA, Wingfield PT, Uhlig HH, Roychoudhuri R, Aitman TJ, Kelleher P, Lenardo MJ, O'Shea JJ, Cooper N, Laurence ADJ
Nat Immunol.
2017 Jul;
18(7).
doi: 10.1038/ni.3753
PMID: 28530713

Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality.

Shih HY, Sciumè G, Mikami Y, Guo L, Sun HW, Brooks SR, Urban JF Jr, Davis FP, Kanno Y, O'Shea JJ
Cell.
2016 May 19;
165(5).
doi: 10.1016/j.cell.2016.04.029
PMID: 27156451

Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.

Schwartz DM, Bonelli M, Gadina M, O'Shea JJ
Nat Rev Rheumatol.
2016 Jan;
12(1).
doi: 10.1038/nrrheum.2015.167
PMID: 26633291

Super-enhancers delineate disease-associated regulatory nodes in T cells.

Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ
Nature.
2015 Apr 23;
520(7548).
doi: 10.1038/nature14154
PMID: 25686607

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