Biology subjects

Kornfeld, H.

Publications and source records attributed to Kornfeld, H..

3 recordsLinked to original sources

bioRxiv2026

NR4A1 limits CD8⁺ T Cell effector responses and protection in tuberculosis

During Mycobacterium tuberculosis (Mtb) infection, CD8+ T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8+ T cell immunity in tuberculosis (TB). Mtb-infected Nr4a1-/- mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8+/CD4+ T cell ratios, and enhanced CD8+ T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of Nkg7+ and Granzyme+ cytotoxic CD8+ T cell subsets in Nr4a1-/- mice. Spatial analyses demonstrated increased infiltration of Nkg7+ activated CD8+ T cells in Nr4a1-/- lesions. ChIP-qPCR showed NR4A1 binding to Nkg7 promoter, and Nkg7 knockdown abrogated the enhanced cytotoxicity of Nr4a1-/- CD8+ T cells. Pharmacologic inhibition of NR4A1 reduced Mtb burden and pathology, and restored Nkg7 expression and CD8+ T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8+ T cell-mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target. A one-sentence summary of your paperNR4A1 suppresses CD8+ T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to Mtb infection.

immunology↗

bioRxiv2023

Neutrophil-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

The protective correlates of Mycobacterium tuberculosis (Mtb) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G+granulocytes (Ly6G+Gra), IL-17 and COX2. We show that in the lungs of Mtb-infected wildtype mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G+Gra-resident four weeks post-infection onwards. In the genetically susceptible IFN{psi} -/- mice, excessive Ly6G+Gra infiltration correlates with severe bacteraemia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G+Gra infiltration, associated pathology and death in IFN{psi} -/- mice. Surprisingly, Ly6G+Gra also serves as the major source of IL-17 in the lungs of Mtb-infected WT or IFN{psi} -/- mice. The IL-17-COX2-Ly6G+Gra interplay also operates in WT mice. Inhibiting ROR{psi}t, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G+Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the Mtb-infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCGs protective efficacy, mainly by targeting the Ly6G+Gra-resident Mtb pool, a phenotype also observed when IL-17 is blocked by ROR{psi}t inhibitor. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6G+Gra axis for TB prevention and therapy.

immunology↗

bioRxiv2020

Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+ T cells

Diabetic patients taking metformin have lower risk for Mycobacterium tuberculosis (Mtb) infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence. However, a detailed mechanistic understanding of metformins protective immunological benefits on host resistance to TB is lacking. In this study, using mass cytometry we show that metformin treatment expands memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy and diabetic humans. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from CXCR3-/- mice did not exhibit metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhanced immunogenicity and protective efficacy against Mtb challenge. Collectively, our results demonstrate an important role of CD8+ T cells in metformin-derived host metabolic-fitness towards Mtb infection.

immunology↗