Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans

Dobeš, Jan; Ben-Nun, Osher; Binyamin, Amit; Stoler-Barak, Liat; Oftedal, Bergithe E.; Goldfarb, Yael; Kadouri, Noam; Gruper, Yael; Givony, Tal; Zalayat, Itay; Kováčová, Katarína; Böhmová, Helena; Valter, Evgeny; Shulman, Ziv; Filipp, Dominik; Husebye, Eystein S.; Abramson, Jakub

doi:10.1038/s41590-022-01247-6

Cited by 36 publications

(32 citation statements)

References 65 publications

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“…6c). RORγt + AIRE + cells have previously been suggested to be related to ILC3s 16,28 , however, the absence of Rag1 fate-mapped Thetis cells suggested that Thetis cells were not descended from the RAG1 + ILC3p identified within our scRNA-seq dataset (Extended Data Fig. 3c).…”

Section: Thetis Cell Ontogenymentioning

confidence: 73%

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Akagbosu

Tayyebi

Shibu

et al. 2022

Nature

122

114

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Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

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Section: Thetis Cell Ontogenymentioning

confidence: 73%

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Akagbosu

Tayyebi

Shibu

et al. 2022

Nature

122

114

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“…6c). RORgt + Aire + cells have previously been suggested to be related to ILC3s 15,26 ; however, the absence of Rag1 fate-mapped TCs suggested that TCs were not descended from the RAG1 + ILC3p identified within our scRNA-seq dataset (Extended data Figure 3c). Furthermore, TCs did not express RORa (Fig.…”

Section: Thetis Cell Ontogenymentioning

confidence: 74%

A novel RORγt⁺ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life

Akagbosu

Tayyebi

Shibu

et al. 2022

Preprint

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Tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. A second wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens within the first few weeks of life, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new lineage of tolerogenic RORγt+Aire+ antigen-presenting cells (APC) with a hybrid dendritic cell (DC)-mTEC phenotype, dubbed Thetis cells (TCs), comprising 4 major sub-groups (TC I-IV). We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While TC I bore remarkable homology with Aire+ mTECs, TC IV were specifically enriched for critical molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was dispensable for pTreg generation, further implicating TCs as the critical tolerogenic RORγt+ APC. Our studies reveal parallel pathways for establishment of tolerance within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.

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“…We have previously demonstrated that upon first encounter with oral C. albicans, IL-17 is expressed almost entirely by tongue-resident γδ + T cells and a population of innately acting CD4 + TCRβ + cells, sometimes termed "natural Th17 cells" (nTh17 cells) (52,53,89). It has been suggested that type 3 innate lymphoid cells may play a role as well (90)(91)(92), though they are extremely rare in the mouth and Rag1 -/mice are highly sensitive to OPC (46,53,93). It should be noted that the oral nTh17 cells that were activated in the 2-to 5-day time frames assessed here are not Candida specific; they exhibit a varied TCR repertoire and do not activate TCR signaling, measured using a Nur77 reporter system that reports TCR signaling strength and duration (46,52,53,93,94).…”

Section: Discussionmentioning

confidence: 99%

A gut-oral microbiome–driven axis controls oropharyngeal candidiasis through retinoic acid

et al. 2022

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Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans

Cited by 36 publications

References 65 publications

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

A novel RORγt⁺ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life

A gut-oral microbiome–driven axis controls oropharyngeal candidiasis through retinoic acid

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Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans

Cited by 36 publications

References 65 publications

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

A novel RORγt+ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life

A gut-oral microbiome–driven axis controls oropharyngeal candidiasis through retinoic acid

Contact Info

Product

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A novel RORγt⁺ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life