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
