Biology subjects

Kronenberg, M.

Publications and source records attributed to Kronenberg, M..

7 recordsLinked to original sources

bioRxiv2026

The metabolic reprogramming of T cells controls airway remodeling in severe asthma

Mixed granulocytic asthma (MGA) is a severe Th2-low endotype, characterized by high Th17/neutrophilic burden and exacerbated airway remodeling. Both features confer resistance to inhaled corticosteroids, and typical asthma treatments. Thus, MGA is an enormous public health burden. Gaps in knowledge include how Th17 cells induce pathological tissue remodeling, and how Th17 differentiation occurs in response to allergens. We generated a Th2-low murine model of asthma that recapitulates major features of human MGA namely, heightened airway reactivity to methacholine, Th17/neutrophilic inflammation, airway remodeling, and resistance to corticosteroid treatment. Two specific biomarkers enriched in human MGA, the TNF superfamily member 14 (aka LIGHT), and the mitochondrial oxidative phosphorylation (OXPHOS) pathway, are upregulated in this model. We show OXPHOS promotes the metabolic reprograming of Th17 cells, to produce LIGHT that controls airway remodeling. Mechanistically, OXPHOS regulates ROR{gamma}t expression and the subsequent transcriptional network to program survival and differentiation of Th17 cells, whereas LIGHT drives airway remodeling by activating the MMP9-dependent TGF{beta} pathway. Additionally, OXPHOS+Th17 cells promote the expression of osteopontin necessary for fibroblast activation. LIGHT antagonistic blockade reduces airway remodeling, whereas OXPHOS chemical inhibition reduces Th17 cells and neutrophilia. Importantly, the dual blockade of LIGHT and OXPHOS reverses all features of MGA and reciprocally increase the numbers of Treg cells. Thus, the dual blockade of LIGHT and OXPHOS constitutes a promising target for clinical interventions in human MGA, possibly extending to other Th17-driven fibrotic diseases.

immunology↗

bioRxiv2024

Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants

Several coinhibitory receptors are upregulated upon activation, whereas a small number of coinhibitory receptors are expressed constitutively by naive T cells. The relationship between constitutively expressed coinhibitors is unknown. We found an inverse relationship between two constitutively expressed coinhibitors, CD5 and BTLA; BTLA expression was low in the thymus and high in the periphery, corresponding respectively with high and low CD5 expression. Germline or induced deletion of Btla in somatic cells demonstrated a causal relationship between BTLA expression and CD5 levels in T cells of central and peripheral lymphoid tissues. The effect of BTLA on CD5 expression on thymic and peripheral CD4 T cells was due to BTLA signaling, rather than signaling by its ligand, the herpes virus mediator (HVEM). Regulation was maintained in mice with a non-signaling HVEM mutant but was lost in Tnfrsf14-/- (Hvem-/-) mice. Increased CD5 levels have been positively associated with increased recognition of self-peptide MHC complexes. Thus, control of CD5 expression by BTLA signals early in T cell ontogeny suggested that BTLA might be important for establishing self-tolerance in newly generated T cells. Consistent with this concept, we found that BTLA, as well as the inducible coinhibitor PD-1, were needed post thymic selection in recent thymic emigrants (RTE) to establish self-tolerance. RTE lacking BTLA caused a multiorgan autoimmune disease whose development required CD4 T cells and MHC class II. Together, our findings identify a negative regulatory pathway allowing constitutively expressed coinhibitory receptors to calibrate their expression in thymic T cell differentiation. Expression of constitutive and induced coinhibitory receptors is needed to establish tolerance in the periphery for RTE.

immunology↗

bioRxiv2021

Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity

Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFN{gamma} (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.

immunology↗

bioRxiv2021

Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung

Innate-like T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and {gamma}{delta} T cells, are present in various barrier tissues, including the lung. They carry out protective responses during infections, but the mechanisms for protection are not completely understood. Here, we investigated their roles during pulmonary infection with Streptococcus pneumoniae. Following infection, innate-like T cells rapidly increased in lung tissue, in part through recruitment, but TCR activation and cytokine production occurred mostly in IL-17-producing NKT17 and {gamma}{delta} T cells. NKT17 cells were preferentially located outside the vasculature prior to infection, as were CD103+ dendritic cells (cDC1), which were important both for antigen presentation to NKT17 cells and {gamma}{delta} T cell activation. Whereas IL-17A-producing {gamma}{delta} T cells also were numerous, GM-CSF was exclusive to NKT17 cells and contributed to iNKT cell-mediated protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.

immunology↗

bioRxiv2021

HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM:LIGHT:CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knock-in mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.

immunology↗

bioRxiv2020

Transcriptome and Chromatin Landscape of iNKT cells are Shaped by Subset Differentiation and Antigen Exposure

Invariant natural killer T cells (iNKT cells) differentiate into thymic and peripheral NKT1, NKT2 and NKT17 subsets. We determined if the gene programs associated with these thymic subsets were maintained in peripheral sites, the influence of tissue location, and if there were large-scale changes after antigen exposure. RNA-seq and ATAC-seq analyses showed that iNKT cells in any subset were similar, regardless of tissue location. Lung iNKT cell subsets possessed the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. After antigenic stimulation, iNKT cells underwent chromatin and transcription changes leading to two populations: one similar to follicular helper T cells and the other like NK or effector cells. Phenotypic analysis indicated these changes were observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to several new subsets.

immunology↗

bioRxiv2020

Epithelial HVEM promotes basement membrane synthesis and intraepithelial T cell survival and migration

Intraepithelial T cells (IET) provide continuous surveillance of the intestinal epithelium, but little was known about how epithelial-derived signals regulate the IET population. We show that epithelial expression of the herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily (TNFRSF), maintained the survival of small intestine IET, especially innate-like TCR{beta}+ cells lacking CD4 and CD8{beta}. Patrolling movement of all CD8+ IET also was impaired in the absence of HVEM. HVEM-deficient epithelial cells exhibited downregulation of synthesis of basement membrane components, including collagen IV. Collagen IV supported IET survival in vitro via interactions with {beta}1 integrins expressed by the IET; absence of {beta}1 integrins decreased some IET subsets. Therefore, these data define a circuit whereby epithelial cells regulate intestine resident T lymphocyte populations through basement membrane synthesis.

immunology↗