The proposed studies will elucidate cellular and molecular mechanisms that organize the activities, fate, and tissue localizations of CD4+ T cells in the lungs. CD4+ T cells are instructed by antigen presentation from MHC-II and costimulatory or checkpoint molecules. Our preliminary data reveal that MHC-II is widely expressed by lung epithelial cells, and dynamically regulated during and after resolution of pneumococcal pneumonia. Furthermore, we observe that distinct sub-types of lung epithelial cells express different patterns of costimulatory and checkpoint molecules. We propose that epithelial cell MHC-II pairs with cell-type-specific expression of costimulatory and checkpoint molecules to appropriately instruct CD4+ T cells, localizing CD4+ T cell activities and all aspects of adaptive immunity that depend on lung CD4+ T cells near more forgiving regions (conducting airways) and away from more fragile and demanding elements (alveoli), to increase immune resistance while diminishing lung injury. Our central hypothesis is that MHC-II on the lung epithelium drives adaptive immunity toward the conducting airways and away from the alveoli, to be tested by pursuing the following specific aims: (1) Test the hypothesis that pulmonary epithelial cells direct the anatomical segregation of CD4+ T cells in the lung. This will be accomplished using multiple microscopy approaches to document the regional kinetics and epithelial interactions of CD4+ cell expansion and contraction during and after pneumonia, RNAseq of epithelial cells that are bright vs. dim for MHC-II, and conditional mutation of MHC-II throughout all the lung epithelium. (2) Test the hypothesis that alveolar epithelial type II cells use MHC- II plus PD-L1 to limit inflammatory lung injury. This will be accomplished using PD-L1 blockade, conditional mutation of MHC-II in alveolar epithelial type II cells, and RNAseq of disparate classes of type II cells with distinct patterns of MHC-II and checkpoint molecules. (3) Test the hypothesis that airway club cells and multiciliated cells use MHC-II plus CD40 to bolster antimicrobial defense. This will be accomplished using conditional mutation of MHC-II or of CD40 in both club cells and multiciliated cells. Altogether, the studies will reveal whether and how lung epithelial cells orchestrate CD4+ T cell activities during pneumonia and determine the TRM cell niche after resolution of infection. Results will identify naturally acquired immune mechanisms that prevent pneumonia in older children and young healthy adults, provide insight into antigen presentation pathways in the lung, and elucidate roles of checkpoint and costimulatory molecules in directing lung CD4+ T cell biology.

Public Health Relevance

The lung contains its own set of immune cells, resident memory T cells, that develop in the lung and stay there, protecting against future infections from related but different microbes that infected the lung previously. How resident memory T cells are instructed, including what factors drive the anatomic distribution of these cells within the lung, is unknown. The proposed studies test whether the epithelial cells that line the insides of the lung and interface with everything that gets inhaled are responsible for instructing resident memory T cells appropriately.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI115053-05
Application #
9818097
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Davidson, Wendy F
Project Start
2015-07-01
Project End
2024-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Smith, N Ms; Wasserman, G A; Coleman, F T et al. (2018) Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol 11:220-235
Hartmann, Nadine; McMurtrey, Curtis; Sorensen, Michelle L et al. (2018) Riboflavin Metabolism Variation among Clinical Isolates of Streptococcus pneumoniae Results in Differential Activation of Mucosal-associated Invariant T Cells. Am J Respir Cell Mol Biol 58:767-776
Mizgerd, Joseph P (2018) Inflammation and Pneumonia: Why Are Some More Susceptible than Others? Clin Chest Med 39:669-676
Quinton, Lee J; Walkey, Allan J; Mizgerd, Joseph P (2018) Integrative Physiology of Pneumonia. Physiol Rev 98:1417-1464
Mizgerd, Joseph P (2017) Pathogenesis of severe pneumonia: advances and knowledge gaps. Curr Opin Pulm Med 23:193-197
Wasserman, Gregory A; Szymaniak, Aleksander D; Hinds, Anne C et al. (2017) Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells. J Clin Invest 127:3866-3876
Coleman, Fadie T; Blahna, Matthew T; Kamata, Hirofumi et al. (2017) Capacity of Pneumococci to Activate Macrophage Nuclear Factor ?B: Influence on Necroptosis and Pneumonia Severity. J Infect Dis 216:425-435
Kozlowski, Elyse; Wasserman, Gregory A; Morgan, Marcos et al. (2017) The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses. PLoS One 12:e0179797
Traber, Katrina E; Symer, Elise M; Allen, Eri et al. (2017) Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol 313:L548-L558
Kamata, Hirofumi; Yamamoto, Kazuko; Wasserman, Gregory A et al. (2016) Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia. Am J Respir Cell Mol Biol 55:407-18