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## Overview

#### Senior Investigator

John O’Shea, M.D.

osheajo@mail.nih.gov

#### Research Areas (IRP Lab Groups)

Cell Biology

Chromosome Biology

Clinical Research

Computational Biology

Genetics and Genomics

Immunology

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.

**Figure 1**
*Eur J Immunol*
33930196

## Cytokine Signaling via STATs

**Figure 2 **
*Rheumatology (Oxford)*
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.
**Figure 3**
*Science*
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

**Figure 4**
*Immunity*
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.

#### Related NIAMS Labs

                                  - Lymphocyte Signaling Unit
                                  - Lymphocyte Transcriptional Regulation Unit

#### Scientific Advances

November 25, 2022

Regulation of Metabolic Programing in T Cells by STAT5 Transcription Factor Protein

#### Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:
                                        - Biodata Mining and Discovery
                                        - Flow Cytometry
                                        - Genomic Technology
                                        - Laboratory Animal Care and Use
                                        - Light Imaging
                                        - Translational Immunology

## Staff

**Credit** Martyn Green

**John O’Shea, M.D.**

osheajo@mail.nih.gov

**Danielle Chisolm, Ph.D.**

danielle.chisolm@nih.gov

**Micala H Hammond**

hammondmh@nih.gov

**Yuka Kanno, M.D., Ph.D.**

kannoy@mail.nih.gov

**Yi-Chu Liao, Ph.D.**

yi-chu.liao@nih.gov

**Tasha A. Morrison, Ph.D.**

tasha.morrison@nih.gov

**Hiroyuki Nagashima, Ph.D.**

hiroyuki.nagashima@nih.gov

**Rachael Philips, Ph.D.**

rachael.philips@nih.gov

**Justin Shayne, B.S.**

justin.shayne@nih.gov

**Kang Yu, Ph.D. **

kang.yu@nih.gov

## Former Lab Members

### U.S. Based

### International

## Image & Media Gallery

##### Working with Dyes

×

Toshiyuki Yamasita, Ph.D., and Yumi Yamashita, Ph.D., working with dyes to visualize proteins on a membrane.

##### The Lab of Molecular Immunology and Inflammation Branch

×

Dr. O’Shea (left) watches as NIAMS visiting fellow Kigoshi Hirahara, M.D., Ph.D., works in the lab of the NIAMS Molecular Immunology and Inflammation Branch.

##### Amanda Poholek, Ph.D., Performs Research

×

Amanda Poholek, Ph.D., performs research on STAT proteins in the Molecular Immunology and Inflammation Branch.

## Scientific Publications

## Selected Recent Publications

###             Microbial ligand-independent regulation of lymphopoiesis by NOD1.        

24(12).

###             Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome.        

388(24).

###             Protein kinases: drug targets for immunological disorders.        

23(12).

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

185(21).

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

54(3).

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

53(4).

###             Translating JAKs to Jakinibs.        

204(8).

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

75(6).

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

51(4).

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

20(7).

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

58(Suppl 1).

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

50(1).

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

363(6422).

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

46(6).

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

18(7).

###             Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality.        

165(5).

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

12(1).

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

520(7548).

## News & Highlights

Press Release | June 1, 2023

### NIH scientists find treatment for rare genetic skin disorder

Read More

Announcement | May 2, 2023

### Scientific Director of Intramural Research, Dr. John O'Shea, Elected to the U.S. National Academy of Sciences

On May 2, 2023, NIAMS Scientific Director of Intramural Research, 

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Announcement | March 24, 2021

### NIAMS’ John O’Shea Awarded 2021 Harrington Prize for Innovation in Medicine

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Featured | March 22, 2021

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

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