Periodic Reporting for period 1 - Stroma.Org (Functional Organization of Immunity by Lymphoid Stromal Cells)
Reporting period: 2020-07-01 to 2022-06-30
The immune system faces an enormous challenge when protecting us – it must provide rapid, tailored immunity to the host without a priori knowledge of when, where and which pathogen will invade. This challenge is further amplified by the fact that the cells that should specifically recognize and fight the pathogen are extremely rare. Hence, the overarching aim of this project was to understand how such rare cells reproducibly detect the presence of pathogens in a timely manner; with the main hypothesis tested being that the lymphoid tissues where immune responses are triggered contain dedicated spatial cellular arrangements (niches) to optimize pathogen recognition and anti-pathogenic responses. Within this framework, we aimed to:
1. Identify and characterize immune cell niches within lymphoid organs that, in the steady-state, optimize immune cell homeostasis and pathogen recognition;
2. Characterize the response of the identified niches to inflammatory stimuli.
By answering these questions, our data is likely to inform on the design of more efficient vaccines that consider the cellular architecture of lymphoid tissues and how they respond to the vaccination/inflammatory stimuli.
Overall, the action is concluded satisfactorily. With minor deviations, its objectives and milestones were achieved resulting, thus far, in the publication 3 original research papers and 1 editorial article.
1. Identify and characterize immune cell niches within lymphoid organs that, in the steady-state, optimize immune cell homeostasis and pathogen recognition;
2. Characterize the response of the identified niches to inflammatory stimuli.
By answering these questions, our data is likely to inform on the design of more efficient vaccines that consider the cellular architecture of lymphoid tissues and how they respond to the vaccination/inflammatory stimuli.
Overall, the action is concluded satisfactorily. With minor deviations, its objectives and milestones were achieved resulting, thus far, in the publication 3 original research papers and 1 editorial article.
This project started from the observation that lymphoid stromal cell (SC) subsets, as identified by single-cell RNA sequencing (scRNAseq), exhibit non-random spatial arrangements. Such spatial arrangements coincided with biased distributions of dendritic cells subsets, which together led to the formation of two distinct cellular niches – Gremlin1+ SCs/cDC2s and CD200+ SCs/cDC1s. Through the combined analysis of the SC and DC transcriptomes, we defined the developmental trajectories of SCs and establish how the different SC and DC subsets might interact with each other. While we were performing these studies, a similar study was published (Kappor et al. Nat.Immunol 2021), which I reviewed and wrote the preview for (Baptista et al., Nat.Immunol 2021). Publication of this manuscript lead us to reorient our efforts to additional immune cell niches identified during our initial analysis. From the identification of a splenic niche where ESAM+ cDC2s and ILC3s co-localize, we went to show that the development of the different splenic cDC subsets is temporally asynchronous with ILC3s, via provision of lymphotoxin, contributing to the size of the overall splenic cDC niche during a restricted timeframe in early development and to the continuous differentiation of ESAM+ cDC2s (Vanderkerken, Baptista et al., JEM 2021). While exploring how this niche responded to inflammatory stimuli, we observed that LPS administration induced rapid re-orientation of lymphocytes from the bloodstream to secondary lymphoid organs. Examination of this phenotype led us to conclude that optimal lymphocyte recruitment into reactive lymphoid organs required sensing of pathogen-derived alarmins by lymph node stromal cells. Upon recognition of such danger signals, lymph node stromal cells upregulated the expression of chemokines and adhesion molecules promoting lymphocyte transmigration into the lymph node parenchyma. This phenomenon, which enriched T cell precursors into the reactive nodes draining sites of infection/pathology, augmented the resulting immune response and hence vaccine efficiency (Baptista et al., submitted).
On collaborative fronts, we reported that liver Kupffer cells are not distributed uniformly but preferentially concentrate near the portal triad. This localization bias, directed by microbiota-induced extracellular matrix remodeling and Cxcl9 chemokine gradient formation, is essential for pathogen capture, preventing infection of the liver’s stem cell rich regions around the central vein and systemic pathogen dissemination (Gola et al., Nature 2021). We also reported on the development of lipid amphiphiles as carriers for targeted drug delivery to the lymph node, showing that the nature and length of the chosen lipid influences lymph node accumulation and immunization efficiency (De Vrieze et al., Adv.Therapeutics 2021).
These results have been exploited/disseminated through 1) publication:
1. Vanderkerken M, Baptista AP, et al. “ILC3s control splenic cDC homeostasis via lymphotoxin signaling.” J Exp Med 218(5):220190835, 2021
2. Baptista et al. “TLR ligand sensing by lymph node stromal cells regulates lymphocyte recruitment into immune responses.” submitted
3. Gola A, et al. “Commensal-driven immune zonation of the liver promotes host defense.” Nature 589(784):131-136, 2021
4. De Vrieze J, Baptista AP, et al. “Lipid nature and alkyl length influence lymph node accumulation of lipid-polyethylene glycol amphiphiles”. Adv. Therap. 2100079, 2021
5. Baptista AP, Gerner MY. “Lymphoid stromal cells proGrem dendritic cell homeostasis”. Nat Immunol 22(5):541-543, 2021 (invited preview)
Or 2) scientific presentation:
1. “Robust control of adaptive immunity.”, Research Institute for Molecular Pathology (IMP), Vienna, Austria (2020)
Or 3) manuscript submission:
1. Baptista et al. “TLR ligand sensing by lymph node stromal cells regulates lymphocyte recruitment into immune responses.” in review
On collaborative fronts, we reported that liver Kupffer cells are not distributed uniformly but preferentially concentrate near the portal triad. This localization bias, directed by microbiota-induced extracellular matrix remodeling and Cxcl9 chemokine gradient formation, is essential for pathogen capture, preventing infection of the liver’s stem cell rich regions around the central vein and systemic pathogen dissemination (Gola et al., Nature 2021). We also reported on the development of lipid amphiphiles as carriers for targeted drug delivery to the lymph node, showing that the nature and length of the chosen lipid influences lymph node accumulation and immunization efficiency (De Vrieze et al., Adv.Therapeutics 2021).
These results have been exploited/disseminated through 1) publication:
1. Vanderkerken M, Baptista AP, et al. “ILC3s control splenic cDC homeostasis via lymphotoxin signaling.” J Exp Med 218(5):220190835, 2021
2. Baptista et al. “TLR ligand sensing by lymph node stromal cells regulates lymphocyte recruitment into immune responses.” submitted
3. Gola A, et al. “Commensal-driven immune zonation of the liver promotes host defense.” Nature 589(784):131-136, 2021
4. De Vrieze J, Baptista AP, et al. “Lipid nature and alkyl length influence lymph node accumulation of lipid-polyethylene glycol amphiphiles”. Adv. Therap. 2100079, 2021
5. Baptista AP, Gerner MY. “Lymphoid stromal cells proGrem dendritic cell homeostasis”. Nat Immunol 22(5):541-543, 2021 (invited preview)
Or 2) scientific presentation:
1. “Robust control of adaptive immunity.”, Research Institute for Molecular Pathology (IMP), Vienna, Austria (2020)
Or 3) manuscript submission:
1. Baptista et al. “TLR ligand sensing by lymph node stromal cells regulates lymphocyte recruitment into immune responses.” in review
Our results have significantly increased knowledge in immunology and host defense. Through them, we redefined the role of ILC3s during development vs. homeostasis vs. perturbation. Thought to work during embryonic/early post-natal development or in the context of infection, our work has shown that ILC3s also play a role during steady-state homeostasis via the continuous provision of lymphotoxin to developing splenic ESAM+ cDC2s. Our work in the lymph node revealed intranodal mechanisms for enhanced immunity based on the differential distribution of immunomodulatory molecules and the role of lymph node stromal cells as sentinels of infection. Our work in the liver has shown that spatial immune cell distribution is a critical parameter in immune cell function, emphasizing the concept of preemptive pre-organization of immune elements for enhanced pathogen recognition and host defense.
Although our results are categorized as general advancement of knowledge and thus are not expected to have immediate socio-economic impact, they are believed to have broad implications for the design of immune-mediated interventions, namely future vaccination efforts.
Although our results are categorized as general advancement of knowledge and thus are not expected to have immediate socio-economic impact, they are believed to have broad implications for the design of immune-mediated interventions, namely future vaccination efforts.