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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

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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.

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