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Type 2 cytokines in the thymus activate Sirpa+ dendritic cells to promote clonal deletion

ABSTRACT: The thymus contains a diversity of dendritic cells (DC) that exist in defined locations and have different antigen processing and presenting features. This suggests that they play non-redundant roles in mediating thymocyte selection. In an effort to eliminate SIRP+ cDC2, we discovered that a substantial proportion expresses the surface lectin, CD301b, in the thymus. These cells resemble the CD301b+ type 2 immune response promoting DC that are present in the skin draining lymph nodes. Transcriptional and phenotypic comparison to other DC subsets in the thymus revealed that thymic CD301b+ cDC represent an activated state that exhibits enhanced antigen processing and presentation. Furthermore, CD301b+ cDC2 demonstrated a type 2 cytokine signature and required steady state IL-4 receptor signaling. Selective ablation of CD301b+ cDC2 impaired clonal deletion without affecting regulatory T cells. TCR alpha repertoire sequencing confirmed that cDC2 promote deletion of conventional T cells with minimal effect on regulatory T cell selection. Together, these findings suggest that cytokine-induced activation of DC in the thymus substantially enforces central tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE198247 | GEO | 2022/05/09

REPOSITORIES: GEO

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Type 2 cytokines in the thymus activate Sirpa+ dendritic cells to promote clonal deletion

Project description:The thymus contains a diversity of dendritic cells (DC) that exist in defined locations and have different antigen processing and presenting features. This suggests that they play non-redundant roles in mediating thymocyte selection. In an effort to eliminate SIRP+ cDC2, we discovered that a substantial proportion expresses the surface lectin, CD301b, in the thymus. These cells resemble the CD301b+ type 2 immune response promoting DC that are present in the skin draining lymph nodes. Transcriptional and phenotypic comparison to other DC subsets in the thymus revealed that thymic CD301b+ cDC represent an activated state that exhibits enhanced antigen processing and presentation. Furthermore, CD301b+ cDC2 demonstrated a type 2 cytokine signature and required steady state IL-4 receptor signaling. Selective ablation of CD301b+ cDC2 impaired clonal deletion without affecting regulatory T cells. TCR alpha repertoire sequencing confirmed that cDC2 promote deletion of conventional T cells with minimal effect on regulatory T cell selection. Together, these findings suggest that cytokine-induced activation of DC in the thymus substantially enforces central tolerance.

2022-03-23 | GSE198789 | GEO

Tissue-specific factors differentially regulate the expression of antigen-processing enzymes during dendritic cell ontogeny

Project description:Dendritic cells (DC) form a collection of antigen-presenting cells that are distributed throughout the body. Conventional DC (cDC) which include the cDC1 and cDC2 subsets, and plasmacytoid DC (pDC) constitute the two major ontogenically distinct DC populations. The pDC complete their differentiation in bone-marrow (BM) while the cDC subsets derive from pre-committed bone-marrow (BM) precursors, the pre-cDC, that seed lymphoid and non-lymphoid tissues where they further differentiate into mature cDC1 and cDC2. Within different tissues, cDC express distinct phenotype and function. Notably cDC in the thymus are exquisitely efficient at processing and presenting antigens in the class II pathway, while in the spleen they do so only upon maturation induced by danger signals. To appraise this functional heterogeneity, we examined the regulation of the expression of distinct antigen-processing enzymes during DC ontogeny. We analyzed the expression of cathepsin S (CTSS), cathepsin L (CTSL) and thymus specific serine protease (TSSP), three major antigen-processing enzymes regulating class II presentation in cDC, by DC BM precursors and immature and mature cDC from spleen and thymus. We found that pre-cDC in the BM express relatively high levels of these different proteases. Then, their expression is modulated in a tissue-specific and subset–specific manner with immature and mature thymic cDC expressing overall higher levels than immature splenic cDC. On the other hand, TSSP expression level is selectively down-regulated in spleen pDC while CTSS and CTSL are both increased in thymic and splenic pDC. Hence tissue-specific factors program the expression levels of these different proteases during DC differentiation thus conferring tissue-specific function to the different DC subsets.

2020-01-29 | GSE144421 | GEO

A lncRNA identifies Irf8 enhancer element in negative feedback control of dendritic cell differentiation

Project description:Dendritic cells (DC) are professional antigen presenting cells that develop from multipotent progenitors (MPP) and DC committed common DC progenitors (CDP) and further differentiate into different subsets: classical DC type 1 and 2 (cDC1 and cDC2, respectively) and plasmacytoid DC (pDC). In this study MPP, CDP, cDC1, cDC2 and pDC were obtained in a two-step in vitro culture system according to Felker et al., J. Immunol. 185, 5326-5335, 2010. Briefly, mouse bone marrow cells were first amplified with a specific cytokine cocktail and then induced to differentiate into DC with Flt3 ligand. MPP, CDP, cDC1, cDC2 and pDC were obtained by FACS sorting as follows: MPP: Gr1- CD117hi CD135low/-; CDP: Gr1- CD117int CD135+ CD115+; cDC1: CD11c+ CD11blow/- XCR1+; cDC2: CD11c+ CD11b+ XCR1- and pDC: CD11c+ CD11b- B220+. FACS sorted cells were then subjected to Omni-ATAC-seq, nuclear-titrated (NuTi) Capture-C targeting Irf8 promoter, and RNA-seq analysis. ATAC-seq data of cDC1 and pDC are published (Li et al., Genome Biol. 20, 45, 2019; GSE118221). ATAC-seq data of MPP, CDP and cDC2, NuTi Capture-C and RNA-seq data of MPP, CDP, cDC1, cDC2 and pDC are published here. CD11c+ CD11b+ B220- cDC and CD11c+ CD11b- B220+ pDC were obtained by FACS sorting and subjected to ChIP-seq analysis of IRF8 and are published here.

2023-03-01 | GSE198651 | GEO

Adult mouse skin dendritic cells

Project description:Early life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here we show that this process is controlled by microbial interaction with a specialized subset of antigen presenting cells. More particularly, we identify CD301b+ type 2 conventional dendritic cells (DC) as a subset in neonatal skin specifically capable of uptake, presentation and generation of regulatory T cells (Tregs) to commensal antigens. In early life, CD301b+ DC2 are enriched for programs of phagocytosis and maturation, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic acid-producing enzyme, RALDH2, deletion of which limited commensal-specific Tregs. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early life tolerance at the cutaneous interface.

2023-01-01 | GSE217891 | GEO

Neonatal foreskin antigen presenting cells after colonization with Staphylococcus epidermidis

2023-01-01 | GSE206893 | GEO

Skin and Skin Draining lymph node dendritic cells from neonatal mouse colonized with a commensal or control

2023-01-01 | GSE206892 | GEO

Mouse neonatal dendritic cells from uncolonized, and Staphylococcus epidermidis-zsgreen colonized mouse (loaded and non-loaded cells)

2023-01-01 | GSE206891 | GEO

Migratory CD11b+ conventional dendritic cells induce T follicular helper cell dependent antibody responses

Project description:T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding the nature of the cDC responsible for instructing Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist, in part, due to the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that we show delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different formulations of antigen delivery, we determined that CD11b+ migratory type 2 conventional DCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2 but not CD103+ cDC1 migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell and antibody development, whereas loss of CD103+ cDC1s in Batf3-/- mice did not. Loss of cDC2-mediated Tfh responses was associated with impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the sub-anatomic regions of the lymph node where Tfh cell priming occurs, the T-B border. This work identifies the DC responsible for Tfh cell-dependent antibody responses, in particular when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.

2017-12-01 | GSE103956 | GEO

Bone marrow-selected antigen specific regulatory B cells

Project description:Autoimmunity is often regarded as pathogenic, but this view has gradually shifted over time. Based on insights from thymus selection, T cells are now known to be selected by self-antigens and positive selection in the thymus medulla leads to regulatory functions. B cells are selected in the bone marrow and the fundamental question is whether self-antigens in the bone marrow select antigen specific regulatory B cells. In this work, we show that B cells are indeed selected for proteins expressed in the bone marrow and develop into cells with regulatory function bearing distinct phenotypic fingerprint. Collagen type II specific regulatory B cells trigger the expansion of antigen specific regulatory T cells and protect against development of tissue specific autoimmune inflammation. These antigen specific regulatory B cells constitute a sizeable fraction of the normal B cell repertoire in both mice and humans.

2023-08-13 | PXD025837 | Pride

Myocardial infarction (MI) primes autoreactive T cells through activation of dendritic cells

Project description:DC subsets of the murine healthy heart consisted of IRF8-dependent conventional (c)DC1, IRF4-dependent cDC2 and monocyte-derived DCs. In steady state, cardiac self-antigen α-myosin was presented in heart-draining mediastinal lymph node (mLN) by cDC1s, driving the proliferation of antigen-specific CD4+ TCR-M T cells, and their differentiation into Tregs. Following MI, all DC subsets infiltrated the heart, while only cDCs migrated to the mLN. Here, cDC2s induced TCR-M proliferation and differentiation into IL-17/IFNγ producing effector cells. Thus, cardiac specific autoreactive T cells get activated by mature DCs following myocardial infarction.

2017-03-15 | GSE94949 | GEO

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