Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation
Abstract
Non-hematopoietic lymph node stromal cells shape immunity by inducing MHC-I-dependent deletion of self-reactive CD8+ T cells and MHC-II-dependent anergy of CD4+ T cells. Here, we show that MHC-II expression on lymph node stromal cells is additionally required for homeostatic maintenance of regulatory T cells (Tregs) and maintenance of immune quiescence. In the absence of MHC-II expression in lymph node transplants, i.e. on lymph node stromal cells, CD4+ as well as CD8+ T cells became activated, ultimately resulting in transplant rejection. MHC-II self-antigen presentation by lymph node stromal cells allowed the non-proliferative maintenance of antigen-specific Tregs and constrained antigen-specific immunity. Altogether, our results reveal a novel mechanism by which lymph node stromal cells regulate peripheral immunity.
Article and author information
Author details
Ethics
Animal experimentation: All animal experiments were reviewed and approved by the Vrije University Scientific and Ethics Committees (protocols MCB09-35, MCB10-01 and MCB13-06). All surgery was performed under xylazine and ketamine anesthesia.
Copyright
© 2014, Baptista et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,555
- views
-
- 481
- downloads
-
- 83
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of ‘younger’ microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.
-
- Immunology and Inflammation
As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.