STAT1 signalling shapes the function of type 2 conventional dendritic cells in lungs of weanling mice. — ASN Events
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  2. Plenary 5: DCs in Mucosal Immunity, Homeostasis & Host Defense
  3. STAT1 signalling shapes the function of type 2 conventional dendritic cells in lungs of weanling mice.

STAT1 signalling shapes the function of type 2 conventional dendritic cells in lungs of weanling mice. (#145)

Kaushikk Ravi Rengarajan 1 2 , Ramin Shakiba 1 2 , Doğuş Altunöz 1 2 , Hamsa Narasimhan 1 2 , Sadiq Nasrah 1 2 , Sabine Schwamberger 3 , Dirk Haller 3 4 , Barbara U. Schraml 1 2
  1. Institut für Immunologie, Biomedizinisches Centrum, Ludwig-Maximilians-Universität München, Planegg-Martinsried (München), Germany
  2. Institut für Kardiovaskuläre Physiologie und Pathophysiologie, Biomedizinisches Centrum, Ludwig-Maximilians-Universität München, Planegg-Martinsried (München), Germany
  3. Core Facility Gnotobiologie, ZIEL Institute for Food & Health, Technische Universität München, Freising, Germany
  4. Chair of Nutrition & Immunology, TUM School of Life Sciences, Technische Universität München, Freising, Germany

Conventional dendritic cells (cDCs) integrate environmental signals to direct T cell immunity or tolerance. In developing lungs of neonatal mice, cytokines push type 2 cDCs (cDC2s) to drive Th2 responses and allergy, while microbial colonisation instructs cDC2s to promote T cell tolerance. Thus, understanding early-life environmental cues could help guide strategies to balance effector priming with tolerance induction.

Here, we performed longitudinal phenotypic and transcriptional profiling from birth until after weaning to define the transcriptional basis underlying the phenotypic and functional heterogeneity of lung cDCs. While type 1 and 2 cDCs could be identified transcriptionally within hours after birth, they acquired several hallmark phenotypic features within the first week of life. Gene set enrichment analyses revealed cytokine-induced pathways such as signalling downstream of interferons (IFNs)  differentially regulated with age in cDC subtypes. Conditional deletion of STAT1 in cDCs using ItgaxCreStat1flox mice confirmed reduced production of the interferon-γ-regulated gene CXCL9 in lung cDC2, but not cDC1, from 3-week-old mice. Concurrently, we observed a reduction of effector-memory (EM) CXCR3⁺ CD4⁺ and CD8⁺ T cells with an antigen-experienced phenotype in lungs, indicating that loss of STAT1 in DCs leads to altered T cell homeostasis against environmental antigens.

We have found that during the transition from breastfeeding to solid food at weaning, IFNγ production from lymphocytes relays dietary information to splenic cDC1 to shape the effector phenotype of food-antigen specific CD8+ T cells in a feed-forward manner. Similarly, we find that while food antigen specific CD8+ T cells accumulate in the lungs of mice weaned onto chow diet and milk diet, these T cells exhibit more pronounced cytotoxic effector function in mice on chow diet. Our studies suggest that an IFN-STAT1 axis shapes cDC2 function in lungs to tune the homeostatic T cell response, with potential implications for oral immunotherapy.