4 results on '"Aditya Ramanujan"'
Search Results
2. Antigen presentation by lung epithelial cells directs CD4+ TRM cell function and regulates barrier immunity
- Author
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Anne Hinds, E.I. Arafa, Anukul T. Shenoy, Thomas Braun, Matthew R. Jones, Carolina Lyon De Ana, Filiz Korkmaz, Aditya Ramanujan, Neelou S. Etesami, Kimberly A. Barker, Hasmeena Kathuria, Joseph P. Mizgerd, Alicia M. Soucy, Anna C. Belkina, Brian R. Tilton, Wesley N. Goltry, I.M.C. Martin, Isabelle Salwig, and Lee J. Quinton
- Subjects
CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,Science ,Cell ,Antigen presentation ,Antigen-presenting cells ,Fluorescent Antibody Technique ,General Physics and Astronomy ,Real-Time Polymerase Chain Reaction ,Immunological memory ,Article ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,Mice ,Immune system ,Microscopy, Electron, Transmission ,Antigen ,Leukocytes ,medicine ,Animals ,Antigen-presenting cell ,Lung ,CD4-positive T cells ,Antigen Presentation ,Multidisciplinary ,medicine.diagnostic_test ,Chemistry ,Epithelial Cells ,General Chemistry ,Flow Cytometry ,Epithelium ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Cytokine ,Mucosal immunology - Abstract
Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity., The maintenance of T resident memory (TRM) cells within pulmonary tissues is incompletely understood. Here the authors show that antigen presentation by lung epithelial cells maintains function and phenotype of pulmonary TRM cells within specific locational niches.
- Published
- 2021
3. Mouse model of late-onset neutrophilic asthma reveals an epithelium-lymphocyte-neutrophil communication circuit underlying destructive airway neutrophilia
- Author
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Anukul T. Shenoy, Filiz Korkmaz, Carolina Lyon De Ana, Christine Odom, Kimberly Barker, Wesley Goltry, Aditya Ramanujan, Ian Martin, Feng-Zhi Shao, Matthew Jones, Lee Quinton, Alan Fine, Felicia Chen, Anna Belkina, and Joseph Mizgerd
- Subjects
Immunology ,Immunology and Allergy - Abstract
While childhood-onset asthma is extensively modeled in labs and includes TH2 cell driven-, steroid-responsive, eosinophilic etiology, little is understood about late-onset asthma which presents as severe, steroid-resistant, and destructive neutrophilic disease with poor outcomes. Lack of appropriate disease models widens this knowledge gap leading to fewer therapies and poorer quality of life for neutrophilic asthma patients. Here, we discover that while conventional models of allergic asthma (relying on naïve sensitized mice acutely challenged with aerosolized ovalbumin) induces eosinophilic asthma, transient and recurrent aeroallergenic exposure over extended durations (as would occur in humans progressing into adulthood) reprograms the lung myeloid and lymphoid landscape to instigate neutrophilic asthma. Mice with such lung history harbor diverse clusters of lung-resident CD4+ TRM cells including a novel RORγt-negative-IL17A+ TH17 subset; the latter detectable in asthmatic adult human lungs. On allergen reencounter, these RORγt-negative TH17 cells, rapidly secrete IL-17A which signals into lung epithelial and stromal cells to express CXCL5 and induce neutrophilic asthma including peribronchial neutrophilia, vascular leakage and lung damage. We find that lung epithelial antigen presentation is crucial to regulate disease severity by skewing CD4+ TRM phenotypes in asthmatic lungs. Specifically, epithelial MHC-II supports TH1 TRM cells and IFNγ secretion; the latter being a potent suppressor of IL-17A-induced CXCL5 and airway neutrophilia. Thus, using a relevant model of the disease, we identify an ‘epithelium-lymphocyte-neutrophil’ circuitry as a critical regulator of late-onset neutrophilic asthma. Supported by NIH grants including HL147461 to F.T.K., HL142199 to K.A.B., HL136725 to M.R.J., GM120060 and HL111449 to L.J.Q., AI115053, HL135756, and HL137081 to J.P.M. and T32 HL007035 for support of trainees.
- Published
- 2022
4. Epithelial antigen presentation regulates CD4+ TRM cell locations, functions and activities
- Author
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Anukul T. Shenoy, Emad I Arafa, Carolina Lyon De Ana, Kimberly A Barker, Filiz T Korkmaz, Aditya Ramanujan, Neelou S Etesami, Ian MC Martin, Brian R Tilton, Anne Hinds, Wesley N Goltry, Hasmeena Kathuria, Matthew R Jones, Lee J Quinton, Anna C Belkina, and Joseph P Mizgerd
- Subjects
Immunology ,Immunology and Allergy - Abstract
Barrier tissues are sentinelled by CD4+ TRM cells with potent anti-microbial activities and considerable lineage plasticity. We hypothesized that local antigen presentation by lung epithelial cells (LECs) instruct CD4+ TRM cell activities. Pneumococcal infections in transgenic mice, flow- and spectral-cytometry, computational biology, and immunofluorescence were used to study this biology. All LECs including a novel alveolar surfactant protein C (SPC)low LEC were adept at antigen presentation. Temporal analysis of LECs for MHC-II and costimulatory/coinhibitory molecules revealed that airway club cells were T-cell stimulatory via CD40 while alveolar LECs expressed T-cell inhibitory PD-L1. This anatomical segregation of LEC antigen presentation correlated with deposition of CD4+ TRM cells around airways such that ablation of LEC MHC-II disrupted CD4+ TRM niches and blockade of CD40 signals prevented accumulation of CD4+ TRM cells. Recurrent memory recalls in absence of LEC MHC-II led to expansion of unconventional CD4+ TRM cells co-expressing classically incompatible lineage-defining transcription factors, changing their cytokine repertoire and leading to dysregulated immunity that phenocopied clinical features of checkpoint blockade therapy. Consequently, a tight correlation between MHC-II and PD-L1 was confirmed in mouse and human LECs. We discovered that LEC MHC-II functions in post-translational trafficking lockstep with PD-L1 to exert its restraints on TRM cell activities. Our results identify epithelial antigen presentation as critical instructors of CD4+ TRM cell locations, phenotypes and activities and establish epithelial-CD4+ TRM cell immunological synapses as key components of barrier immunity.
- Published
- 2021
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