No bones about it: regulatory T cells promote fracture healing

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Abstract

Regulatory T cells (Tregs) are increasingly being recognized for their role in promoting tissue repair. In this issue of the JCI, Chen et al. found that Tregs at the site of bone injury contribute to bone repair. The CCL1/CCR8 chemokine system promoted the accumulation of Tregs at the site of bone injury, where Tregs supported skeletal stem cell (SSC) accumulation and osteogenic differentiation. CCL1 increased the transcription factor basic leucine zipper ATF-like transcription factor (BATF) in CCR8 ⁺ Tregs, which induced the secretion of progranulin that promoted SSC osteogenic function and new bone formation. This study highlights the ever-expanding role of Tregs in tissue repair by demonstrating their ability to expand stem cells at a site of injury.

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Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation

Niwa Ali, Bahar Zirak, Robert Rodriguez … (2017)

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of T regs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.

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T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Moshe Biton, Adam L. Haber, Noga Rogel … (2018)

In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.

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Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019

(2021)

Background Bone fractures are a global public health issue; however, to date, no comprehensive study of their incidence and burden has been done. We aimed to measure the global, regional, and national incidence, prevalence, and years lived with disability (YLDs) of fractures from 1990 to 2019. Methods Using the framework of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we compared numbers and age-standardised rates of global incidence, prevalence, and YLDs of fractures across the 21 GBD regions and 204 countries and territories, by age, sex, and year, from 1990 to 2019. We report estimates with 95% uncertainty intervals (UIs). Findings Globally, in 2019, there were 178 million (95% UI 162–196) new fractures (an increase of 33·4% [30·1–37·0] since 1990), 455 million (428–484) prevalent cases of acute or long-term symptoms of a fracture (an increase of 70·1% [67·5–72·5] since 1990), and 25·8 million (17·8–35·8) YLDs (an increase of 65·3% [62·4–68·0] since 1990). The age-standardised rates of fractures in 2019 were 2296·2 incident cases (2091·1–2529·5) per 100 000 population (a decrease of 9·6% [8·1–11·1] since 1990), 5614·3 prevalent cases (5286·1–5977·5) per 100 000 population (a decrease of 6·7% [5·7–7·6] since 1990), and 319·0 YLDs (220·1–442·5) per 100 000 population (a decrease of 8·4% [7·2–9·5] since 1990). Lower leg fractures of the patella, tibia or fibula, or ankle were the most common and burdensome fracture in 2019, with an age-standardised incidence rate of 419·9 cases (345·8–512·0) per 100 000 population and an age-standardised rate of YLDs of 190·4 (125·0–276·9) per 100 000 population. In 2019, age-specific rates of fracture incidence were highest in the oldest age groups, with, for instance, 15 381·5 incident cases (11 245·3–20 651·9) per 100 000 population in those aged 95 years and older. Interpretation The global age-standardised rates of incidence, prevalence, and YLDs for fractures decreased slightly from 1990 to 2019, but the absolute counts increased substantially. Older people have a particularly high risk of fractures, and more widespread injury-prevention efforts and access to screening and treatment of osteoporosis for older individuals should help to reduce the overall burden. Funding Bill & Melinda Gates Foundation.

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Jason W. Griffith

Andrew D. Luster:

ORCID: https://orcid.org/0000-0001-9679-7912

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J Clin Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date (Electronic, pub): 16 January 2025

Publication date (Electronic, collection): 16 January 2025

Publication date PMC-release: 16 January 2025

Volume: 135

Issue: 2

Electronic Location Identifier: e188368

Affiliations

[1 ]Center for Immunology and Inflammatory Diseases,

[2 ]Division of Pulmonary & Critical Care Medicine, and

[3 ]Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Author notes

Address correspondence to: Andrew Luster, CNY 149-8.304, 149 13th Street, Charlestown, Massachusetts, 02129, USA. Phone: 617.726.5710; Email: aluster@ 123456mgh.harvard.edu .

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Andrew D. Luster https://orcid.org/0000-0001-9679-7912

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Publisher ID: 188368

DOI: 10.1172/JCI188368

PMC ID: 11735088

PubMed ID: 39817452

SO-VID: 4a4be7c7-0ecc-4ca7-8e2c-c484ae3e4874

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This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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No bones about it: regulatory T cells promote fracture healing

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Most cited references 19

Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation

T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019

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