Highlights of the ERS Lung Science Conference 2022

This article presents the highlights of the ERS Lung Science Conference 2022, including a session organised by the Early Career Member Committee (ECMC) dedicated to career development https://bit.ly/3tarCXc Every year, the European Respiratory Society (ERS) organises the Lung Science Conference (LSC), in Estoril, to discuss basic and translational science. The topic of the 20th LSC was “Mucosal immunology of the lung: balancing protective immunity and chronic inflammation”. This was the first time that the LSC was organised as a hybrid congress with both in person and online attendance. In addition to an outstanding scientific programme, the LSC provides excellent opportunities for career development and inclusion of early career members (ECMs). All scientific and poster sessions are chaired by an ECM who is paired with a senior faculty to allow ECMs to become acquainted with session chairing, and there is a session organised by the Early Career Member Committee (ECMC) dedicated to career development. Moreover, travel bursaries are made available to abstract authors, and all bursary recipients and first-time attendees are invited to take part in a mentorship lunch. In this article, we provide the names of the ECM awardees and describe the scientific highlights of the LSC 2022 for those who could not attend.info:eu-repo/semantics/publishedVersio

Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study.

Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR [aOR] 0.65 [95% CI 0.44-0.95]), ruxolitinib as first- vs second- or later-line therapy (40.2% vs 31.5%; aOR 0.53 [95% CI 0.38-0.75]), and a ruxolitinib total daily dose at Week 12 of20 mg/day vs ≤20 mg/day (41.3% vs 30.4%; aOR 0.47 [95% CI 0.33-0.68]). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement.Trial registrationINC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP).2010-024473-39; NCT01493414Date of registration: 16 December 2011https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-024473-39https://clinicaltrials.gov/ct2/show/NCT01493414

Antigen presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal-associated bacteria

Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell-dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell-dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell-dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota

Origin and ontogeny of human lung macrophages

The lung is a vital organ occupied by a large diversity of immune cells due to its close proximity with the external environment. This thesis focuses on a particular type of immune cell: the macrophage. The lungs are composed of three separate anatomical compartments: the airways that start from the trachea and end at the alveoli, the blood capillaries and the connective tissue supporting the lung structure. Correspondingly, three macrophage subsets have been described in the lungs: alveolar, intravascular and interstitial macrophages. Contrary to the reigning dogma that macrophages were generated from circulating monocytes, studies in mice demonstrated that fetal monocytes seeding the lungs during embryonic stages gave rise to alveolar macrophages after birth. The origin of lung macrophages in humans remains unknown as invasive experiment to track cellular origin in vivo are ethically impossible to conduct. To face this challenge, we used the MISTRG humanized mouse model. MISTRG mice support the development of human myeloid cells (especially human monocytes and macrophages). MISTRG mice were transplanted intrahepatically, intranasally and intravenously with different adult and embryonic precursors to assess their macrophage progenitor capacity as well as migration potential. In addition, we performed intravascular cell labelling, bead-based fate-mapping, microarray gene expression analysis, bulk and single-cell RNA sequencing to investigate the precise localization of macrophage progenitors and the heterogeneity of the human lung macrophage compartment. We demonstrated in Paper I that two distinct developmental pathways from circulating blood monocytes exist: CD14+ CD16- classical monocytes give rise to interstitial and alveolar macrophages while their CD14low CD16+ non-classical counterparts generate pulmonary intravascular macrophages. In Paper II, we defined the CD116+ CD64- human fetal progenitor of alveolar macrophages, resembling Myb-expressing erythro-myeloid progenitors (EMPs) and CD64- myeloid progenitors derived from EMPs in mice. These fetal progenitors had a highly proliferative gene expression profile and were consequently better at occupying the alveolar niche than the adult monocytes. Gene expression analysis of alveolar macrophages of adult and embryonic origin revealed that the environment had a strong impact on macrophage function as very few genes were differentially expressed between alveolar macrophages of different origin. However, adult precursors preferentially generated interferon-responsive macrophages, similar to a subset expanding in inflammatory disease in humans such as COVID-19. This thesis provides new insights into the origin and development of human lung macrophages, thereby contributing to the development of macrophage-based therapies for lung diseases in humans

CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages

International audienceDespite their importance in lung health and disease, it remains unknown how human alveolar macrophages develop early in life. Here we define the ontogeny of human alveolar macrophages from embryonic progenitors in vivo, using a humanized mouse model expressing human cytokines (MISTRG mice). We identified alveolar macrophage progenitors in human fetal liver that expressed the GM-CSF receptor CD116 and the transcription factor MYB. Transplantation experiments in MISTRG mice established a precursor–product relationship between CD34−CD116+ fetal liver cells and human alveolar macrophages in vivo. Moreover, we discovered circulating CD116+CD64−CD115+ macrophage precursors that migrated from the liver to the lung. Similar precursors were present in human fetal lung and expressed the chemokine receptor CX3CR1. Fetal CD116+CD64− macrophage precursors had a proliferative gene signature, outcompeted adult precursors in occupying the perinatal alveolar niche, and developed into functional alveolar macrophages. The discovery of the fetal alveolar macrophage progenitor advances our understanding of human macrophage origin and ontogeny

Distinct developmental pathways from blood monocytes generate human lung macrophage diversity

The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo

Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation

International audienceGroup 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis