About

Dr. John Chang studies the cellular and molecular mechanisms underlying T lymphocyte fate specification. His research focuses on understanding how activated T lymphocytes give rise to differentially fated progeny, addressing a central problem faced by multi-cellular organisms: the need for rare progenitor cells to continually produce terminally differentiated cells while preserving a self-renewing lineage. In the mammalian immune system, this challenge is exemplified by T lymphocytes, which must simultaneously differentiate and regenerate. Dr. Chang's work aims to elucidate the molecular mechanisms that enable this balance in T lymphocyte populations. He has been recognized with several prestigious awards, including the HHMI Physician-Scientist Early Career Award, the NIH Director's New Innovator Award, and the AGA-GRG Young Investigator Award in Basic Science. Additionally, Dr. Chang has been elected to the American Society for Clinical Investigation (ASCI) and is supported by grants from the National Institutes of Health and the Kenneth Rainin Foundation.

Research topics

• Biology
• Genetics
• Immunology
• Medicine
• Bioinformatics
• Pathology
• Neuroscience
• Biochemistry
• Computational biology
• Chemistry
• Physiology

Selected publications

• IL-23p19 Antagonists vs Ustekinumab for Treatment of Crohn's Disease: A Meta-Analysis of Randomized Controlled Trials

  The American Journal of Gastroenterology · 2025-03-12 · 10 citations

  articleOpen access

  INTRODUCTION: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing interleukin (IL)-23p19 antagonists with ustekinumab, stratified by prior biologic exposure, in patients with moderate-to-severe Crohn's disease (CD). METHODS: Through a systematic review through August 17, 2024, we identified phase 2 and 3 RCTs comparing IL-23p19 antagonists vs ustekinumab in adults with moderate-to-severe CD. The primary outcome was achieving clinical remission at ∼1 year, and secondary outcomes were achieving endoscopic remission and serious adverse events. We performed subgroup analyses based on prior exposure to biologic therapy, primarily tumor necrosis factor antagonists. Certainty of evidence was appraised using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: We included 5 head-to-head RCTs with a treat-through design (n = 2,506), of which 1 was conducted exclusively in patients with prior tumor necrosis factor antagonist exposure. On meta-analysis, patients treated with IL-23p19 inhibitors may be more likely to achieve clinical remission (relative risk [RR], 1.18 95% confidence interval [CI] 1.02-1.36) (low certainty of evidence) and endoscopic remission (RR 1.53, 95% CI 1.07-2.20) compared with ustekinumab. On subgroup analysis, IL-23p19 antagonists are probably more efficacious than ustekinumab in patients with prior biologic exposure (clinical remission: RR 1.31, 95% CI 1.16-1.48; endoscopic remission: RR 1.61, 95% CI 1.27-2.05) (moderate to high certainty), but not in biologic-naive patients (clinical remission: RR 0.99, 95% CI 0.90-1.08; endoscopic remission: RR 1.16, 95% CI 0.82-1.65). IL-23p19 antagonists may be associated with a lower risk of serious adverse events as compared with ustekinumab (RR 0.79, 95% CI 0.61-1.02). DISCUSSION: IL-23p19 antagonists are probably more efficacious and safer than ustekinumab in patients with moderate-to-severe CD in patients with prior biologic exposure, but not in biologic-naive patients.

  PublisherOA PDFDOI

• Animal-Origin Free Medium for hPSC derived CD8 SP-T Cell Generation

  Cytotherapy · 2025-04-30

  article
  PublisherDOI

• Efficacy of Advanced Therapies in Achieving Remission by Disease Location in Crohn’s Disease: A Systematic Review and Meta-analysis

  Clinical Gastroenterology and Hepatology · 2025-07-23 · 10 citations

  review
  PublisherDOI

• Foxo1 regulates intestinal tissue–resident memory CD8 T cell biology in an anatomic compartment– and context-specific manner

  Science Immunology · 2025-04-11 · 5 citations

  articleOpen accessSenior authorCorresponding

  Tissue-resident memory CD8 T (T RM ) cells serve as a front-line defense against microbial pathogens in barrier and mucosal tissues. Accurately predicting the roles of tissue-specific transcription factors (TFs) that regulate T RM biology remains a challenge. Here, by applying integrated transcriptomic and epigenomic analyses, we have identified an unexpected role for forkhead box O1 (Foxo1), a TF previously known to regulate circulating memory T cells, in intestinal T RM biology. Foxo1 repressed the maintenance of early small intestinal intraepithelial T RM cells in contrast with its actions in sustaining T RM cells from small intestinal lamina propria and colon and contrary to its broader role in promoting intestinal T RM cell formation. These findings highlight the emerging concept that the transcriptional regulation of T RM cells may be more complex and nuanced than previously appreciated and underscore the utility of integrated transcriptomic and epigenomic analyses in reconstructing TF-regulatory networks.

  PublisherOA PDFDOI

• Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted

  Nature · 2025-01-22 · 67 citations

  articleOpen access

  Abstract Tissue-resident memory CD8 T (T RM ) cells provide protection from infection at barrier sites. In the small intestine, T RM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential 1 . However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the phenotypic heterogeneity of T RM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific T RM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct T RM cell states: differentiated T RM cells and progenitor-like T RM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand–receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.

  PublisherDOI

• IMPACT OF TREATMENT RESPONSE WITH ADALIMUMAB ON RISK OF SERIOUS INFECTIONS IN PATIENTS WITH CROHN’S DISEASE: SECONDARY ANALYSIS OF THE PYRAMID REGISTRY

  Inflammatory Bowel Diseases · 2024-01-25

  articleOpen access

  Abstract BACKGROUND AND AIMS Treatment efficacy and safety are primary factors in choosing therapies in patients with Crohn’s disease (CD). However, they can be perceived to be at odds with each other with more potent therapies associated with increased risk of infections. We evaluated the impact of treatment response on the risk of serious infections in adalimumab-treated patients with CD through secondary analysis of the PYRAMID registry. METHODS We included patients with CD who newly started adalimumab in the prospective PYRAMID registry (NCT00524537) and classified them as treatment responders (achieved steroid-free clinical remission based on patient-reported outcomes) vs. non-responders (not in steroid-free clinical remission) at 6m after treatment initiation (landmark). We compared the risk of serious infections between responders vs. non-responders between 6-36m after treatment initiation, through stabilized inverse probability of treatment weighted (IPW) Cox proportional hazards model. RESULTS Of 1515 adalimumab-treated patients with complete data at 6m, 763 (50.4%) were classified as responders (37±13y, 56% female, disease duration, 9.5y). At time of starting adalimumab (baseline), as compared with non-responders, responders were less likely to have moderate to severe symptoms (55.6% vs. 33%), require steroids (45.5% vs. 17.3%) or opiates (6.6% vs. 1.3%), have had prior CD-related surgery (46.5% vs. 35.1%), without any differences in disease location, perianal disease, and prior CD complications. On follow-up, between 6-36m (observation period after 6m landmark), 123 patients experienced a total of 162 serious infections. Of these, 52 responders (6.8%) experienced a serious infection vs. 71 non-responders (9.4%). Approximately, 58% infections were classified as gastrointestinal in origin. On stabilized IPTW through generalized boosting model, responders were 34% less likely to experience serious infections on follow-up compared with non-responders (HR, 0.66; 95% CI, 0.46-0.96). There was no significant difference in risk of serious infections between responders vs. non-responders based on organ site (gastrointestinal infections: HR, 0.61; 95% CI, 0.38-0.99; extra-intestinal infections: HR, 0.61; 95% CI, 0.46-1.30) (p-value for difference in groups = 1.00). Responders were significantly less likely to require corticosteroids on follow-up (1y: 4.4%, 2y: 8.9%, 3y: 9.6%), compared with non-responders (1y: 50.7%, 2y: 51.6% vs. 3y: 51%). CONCLUSIONS Patients with CD who respond to adalimumab have lower risk of developing serious infections, compared with non-responders, after accounting for disease severity. These findings underscore that initiation of advanced therapy for CD may lower the risk of serious infections through effective disease control and avoidance of corticosteroids.

  PublisherOA PDFDOI

• Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-25 · 4 citations

  preprintOpen access

  Tissue-resident memory CD8 T cells (T RM ) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) T RM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct T RM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific T RM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. T RM populations were spatially segregated: with more effector- and memory-like T RM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain T RM differentiation and functional diversity, including different TGFβ sources. Alterations in the cellular networks induced by loss of TGFβRII expression revealed a model consistent with TGFβ promoting progressive T RM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

  PublisherOA PDFDOI

• Correction to: Genetic Risk, Dysbiosis, and Treatment Stratification Using Host Genome and Gut Microbiome in Inflammatory Bowel Disease

  Clinical and Translational Gastroenterology · 2024-12-01

  erratumOpen access
  PublisherDOI

• Automated Spatial Omics Landscape Analysis Approach Reveals Novel Tissue Architectures in Ulcerative Colitis

  Research Square · 2024-03-11 · 1 citations

  preprintOpen access
  PublisherOA PDFDOI

• Impact of Treatment Response on Risk of Serious Infections in Patients With Crohn’s Disease: Secondary Analysis of the PYRAMID Registry

  Clinical Gastroenterology and Hepatology · 2024-01-11 · 13 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R00LM009837

  NIH · $699k · 2014

• Role of proteasome activity in adaptive immunity

  NIH · $2.2M · 2017–2023

• Role of atypical Protein Kinase C in Inflammatory Bowel Disease

  NIH · $1.7M · 2012–2018

• Interrogating adaptive immunity to microbial infection

  NIH · 2016–2020

• NIH Grant K08DK080949

  NIH · $723k · 2013

Frequent coauthors

• Brigid S. Boland

  64 shared

• Steven L. Reiner

  Columbia University Irving Medical Center

  52 shared

• Ichiko Kinjyo

  University of New Mexico

  38 shared

• Sarah M. Russell

  Peter MacCallum Cancer Centre

  35 shared

• William J. Sandborn

  32 shared

• Jane Oliaro

  Peter MacCallum Cancer Centre

  31 shared

• V. Palanivel

  29 shared

• Ananda W. Goldrath

  University of California, San Diego

  28 shared