Biology subjects

Colombo, S. A.

Publications and source records attributed to Colombo, S. A..

3 recordsLinked to original sources

bioRxiv2026

IL4Ra Controls The Medullary Dwell Time Of Mature Thymocytes By Scheduling Their Release From The Thymus

Following their generation, newly produced single positive (SP) thymocytes must remain in the thymus to undergo post-selection maturation, a process supported by the thymic medulla. This ensures that SP thymocytes are equipped with functional competence prior to S1PR1-mediated thymic emigration. Despite this importance, the intrathymic mechanisms that control the balance between retention and release of SP thymocytes is unclear. Here, we describe a cell autonomous requirement for IL4Ra-signalling in SP thymocytes, that determines the duration of their medullary occupancy. We show that the period of this occupancy is prolonged in the absence of IL4R expression by SP thymocytes, which occurs as a result of impaired interactions with medullary thymic epithelial cells (mTEC). Importantly, extending the duration of medullary occupancy enhances the maturational status and functional capabilities of SP thymocytes, including improved TNF and IL2 production. Collectively, we show that IL4Ra regulates the medullary occupancy of mature thymocytes, which in turn determines the functional properties of thymic output.

immunology↗

bioRxiv2025

Pulmonary macrophage subsets display distinct metabolic responses to polarising stimuli in vivo

Macrophage activation is underpinned by metabolic changes required to fight infection, resolve inflammation and enable effective wound healing. While metabolic control of macrophage activation is increasingly understood in culture systems in vitro, it remains poorly understood in more complex in vivo settings, like the lung. Here we applied novel flow cytometry based immunometabolic techniques to profile immune cell metabolism in the murine lung. We revealed a surprising role for glucose in naive alveolar macrophages (AMs) that was retained by AMs polarised in vivo with either interleukin-4 (IL-4) or lipopolysaccharide (LPS). We identified that naive interstitial macrophages (IMs) were dependent on mitochondrial and glucose metabolism, IMs polarised with IL-4 failed to induce metabolic alterations but displayed a glycolytic phenotype following LPS exposure as they adopted an M1 like metabolic profile. We also demonstrated that AMs were metabolically less responsive than IMs to intranasal delivery of LPS, but upregulated glycolysis and metabolic features of M2 polarisation (defined in vitro) in response to intranasal IL-4, including oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and arginine metabolism. Finally, we identified AM M2 polarisation as highly sensitive to glucose inhibition ex vivo. Thus, lung macrophage subsets display distinct metabolic responses to polarising stimuli in vivo. HighlightsO_LINaive alveolar macrophages require glucose metabolism despite residing in a low glucose environment. C_LIO_LIAlveolar macrophages are more responsive to IL-4 in vivo than LPS upregulating oxidative metabolism, lipid metabolism and glycolysis. C_LIO_LIInterstitial macrophages adopt a glycolytic phenotype characteristic of M1 BMDMs in vitro following in vivo LPS administration. C_LIO_LIAlternatively activated alveolar macrophages are extremely sensitive to glucose inhibition ex vivo. C_LI

immunology↗

bioRxiv2019

IL-17A both initiates (via IFNγ suppression) and limits the pulmonary type 2 immune response to nematode infection

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production and neutrophilia. Using N. brasiliensis infection we confirm previous observations that Il17a-KO mice exhibit an impaired type-2 immune response. Neutrophil depletion and reconstitution studies demonstrated that neutrophils contribute to the subsequent eosinophilia but are not responsible for the ability of IL-17A to promote type-2 cytokine responses. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifn{gamma} signature in the Il17a-KO mice confirmed by enhanced IFN{gamma} protein production. Depletion of early IFN{gamma} rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFN{gamma} promotes type-2 immunity. Notably, when IL-17A was blocked later in infection, the type-2 response increased. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when a parasite lifecycle is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity which supports the development of a protective type-2 immune response but subsequently limits the magnitude of that response.

immunology↗