Biology subjects

Webb, G. R.

Publications and source records attributed to Webb, G. R..

3 recordsLinked to original sources

bioRxiv2026

IL-2- and IL-4-dependent signaling play separate and sequential roles in the differentiation of GATA3-hi TH2 cells in vivo

Naive CD4+ T cells differentiation into T-helper type 2 (TH2) cells requires Interleukin 2 (IL-2) and IL-4-dependent signaling as well as presentation of allergens by dendritic cells (DCs). The role of IL-2 and IL-4 in TH2 differentiation has been mostly studied in vitro, however, these models do not account for the heterogeneity of TH responses and bypass the DC-derived signals that are necessary in vivo. We used cytokine-blocking antibodies and IL-4RKO/IL-4RWT mixed bone marrow chimeras to show that IL-4 signaling was not required for initial upregulation of GATA3 by CD4+ T cells after intradermal immunization, but was necessary for later TH2 cell expansion and further GATA3 upregulation. Single-cell transcriptomics and computational analyses confirmed that IL-4 signaling was not necessary for TH2 identity but promoted TH2 proliferation and expression of a pathogenic signature. Early IL-2 blockade prevented GATA3 upregulation without affecting TH2 proliferation or the differentiation of TH1 and TFH subsets after immunization. Adoptive transfer experiments showed that reduced competition for IL-4 in vivo drove extensive T cell proliferation and preferential expansion of the GATA3hi population. Overall, our results suggest temporally and functionally distinct roles of IL-2 and IL-4 during TH2 differentiation: IL-2 is necessary for GATA3 upregulation, while IL-4 drives subsequent TH2 proliferation and licensing to effector activity. Therefore, IL-2 and IL-4 act in a co-ordinated manner to respectively promote TH2 differentiation, expansion, and effector commitment in the LN.

immunology↗

bioRxiv2024

IFN-I signaling in type 2 conventional dendritic cells supports TH2 and T follicular helper differentiation after allergen immunization

Type 2 dendritic cells (DC2s) are essential for TH2 differentiation, but the signaling pathways involved in allergen sensing, DC activation and instruction of CD4+ T cell priming remain unclear. Previous transcriptomic analyses demonstrated a type-I interferon (IFN-I) signature in skin cDC2s following immunization with non-viable larvae of Nippostrongylus brasiliensis (Nb), house dust mite (HDM), and Schistosoma egg antigen (SEA). Blocking IFN-I signaling with anti-IFNAR1 (aIFNAR1) led to reduced TH2 cytokine responses to these antigens, however, the phenotype of cytokine-producing CD4+ T cells was not further defined. Here we show that conditional loss of IFNAR1 signaling in CD11c+ DCs significantly impaired effector TH2 and TFH CD4+ T cell responses to Nb. In vivo proliferation experiments demonstrated reduced numbers of highly divided CD4+ T cells in IFNAR1{Delta}CD11c mice compared to IFNAR1WT, with the highly divided population comprising both TH2 and TFH. Characterization of the cDC2 compartment by flow cytometry and bulk RNAseq demonstrated lower numbers of Nb+ cDC2s in the skin-draining LN and a reduced expression of Il15 and Il15Ra in IFNAR1{Delta}CD11c mice compared to IFNAR1WT, while expression of costimulatory molecules including CD80, CD86, Cd40 and Pdcd1lg2 (PD-L2) was not impaired. Therefore, IFN-I conditioning of skin cDC2s is necessary for their effective priming of CD4+ T cell responses to allergens, providing evidence for a role of tissue cytokines in driving cDC2 activation in a TH2 context.

immunology↗

bioRxiv2021

The skin environment controls local dendritic cell differentiation and function through innate IL-13

The signals driving the adaptation of type-2 dendritic cells (DC2s) to diverse peripheral environments are not well understood. We show that the development of CD11blow migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11bhi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ ROR{gamma}t+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.

immunology↗