Resolving Resident Colonic Muscularis Macrophage Diversity and Plasticity During Colitis.

BACKGROUND: Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation. METHODS: This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ). RESULTS: In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified. CONCLUSIONS: Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs.

Involvement of the muscularis propria accompanies a poorer prognosis in IBD. This study characterizes muscularis macrophage subpopulations during colitis, highlighting the loss of anti-inflammatory LYVE-1+ macrophages and inflammatory plasticity in resident CX3CR1+ macrophages, providing insights into prognostic and therapeutic targets.

Antigen-specific T cell responses in SARS-CoV-2 mRNA-vaccinated children.

SARS-CoV-2 mRNA vaccines elicit humoral responses in children that are comparable to those in adults. However, early-life T cell responses are distinct from adult ones, and questions remain about the nature and kinetics of mRNA vaccine-induced T cell responses in children. We report that Pfizer BNT162b2 mRNA vaccination elicits a significant antigen-specific CD4+ T cell response in the ≥12-year-old cohort. This response is weaker in magnitude in the 5- to 11-year-old cohort and is not improved by a higher vaccine dose (Moderna mRNA1273, 100 µg), suggesting distinct developmental programming that may underscore early-life T cell immunity. Increased effector phenotypes of antigen-specific T cells in younger children correspond with elevated anti-receptor binding domain antibody levels, albeit at the cost of memory generation. These studies highlight aspects of age-specific adaptive immune responses and the need for careful consideration of priming conditions including vaccine dose and adjuvant in the pediatric population.

RXRα Regulates the Development of Resident Tissue Macrophages.

Resident tissue macrophages (RTMs) develop from distinct waves of embryonic progenitor cells that seed tissues before birth. Tissue-specific signals drive a differentiation program that leads to the functional specialization of RTM subsets. Genetic programs that regulate the development of RTMs are incompletely understood, as are the mechanisms that enable their maintenance in adulthood. In this study, we show that the ligand-activated nuclear hormone receptor, retinoid X receptor (RXR)α, is a key regulator of murine RTM development. Deletion of RXRα in hematopoietic precursors severely curtailed RTM populations in adult tissues, including the spleen, peritoneal cavity, lung, and liver. The deficiency could be traced to the embryonic period, and mice lacking RXRα in hematopoietic lineages had greatly reduced numbers of yolk sac and fetal liver macrophages, a paucity that persisted into the immediate postnatal period.