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Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (B RM ) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4 + T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4 + cells, and CD40 ligand (CD40L) signaling were all needed for lung B RM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung B RM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4 + T cells in the infected lung is critical to establishment of local B RM cells, which subsequently protect the airways and parenchyma against future potential infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Etesami, Barker, Shenoy, De Ana, Arafa, Grifno, Matschulat, Vannini, Pihl, Breen, Soucy, Goltry, Ha, Betsuyaku, Browning, Varelas, Traber, Jones, Quinton, Maglione, Nia, Belkina and Mizgerd.)

Streptococcus pneumoniae is the most common etiology of bacterial pneumonia, one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with S. pneumoniae, lymphocytes accumulate in the lungs and protect against reinfection with serotype-mismatched strains. Cluster of differentiation CD4 + resident memory T (T RM ) cells are known to be crucial for this protection, but the diversity of lung CD4 + T RM cells has yet to be fully delineated. We aimed to identify unique subsets and their contributions to lung immunity. After recovery from pneumococcal infections, we identified a distinct subset of CD4 + T cells defined by the phenotype CD11a hi CD69 + GL7 + in mouse lungs. Phenotypic analyses for markers of lymphocyte memory and residence demonstrated that GL7 + T cells are a subset of CD4 + T RM cells. Functional studies revealed that unlike GL7 - T RM subsets that were mostly (RAR-related Orphan Receptor gamma T) RORγT + , GL7 + T RM cells exhibited higher levels of (T-box expressed in T cells) T-bet and Gata-3, corresponding with increased synthesis of interferon-γ, interleukin-13, and interleukin-5, inherent to both T helper 1 (T H 1) and T H 2 functions. Thus, we propose that these cells provide novel contributions during pneumococcal pneumonia, serving as important determinants of lung immunity., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Barrier tissues are populated by functionally plastic CD4 + resident memory T (T RM ) cells. Whether the barrier epithelium regulates CD4 + T RM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC) low MHC high 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 + T RM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4 + T RM 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 + T RM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4 + T RM cell function and identify epithelial-CD4 + T RM cell immune interactions as core elements of barrier immunity., (© 2021. The Author(s).)