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

Breed, Elise R.; Vobořil, Matouš; Ashby, Katherine; Martinez, Ryan; Qian, Lily; Wang, Haiguang; Salgado, Oscar Camilo; O’Connor, Christine H.; Hogquist, Kristin A.

doi:10.1038/s41590-022-01218-x

Cited by 29 publications

(34 citation statements)

References 62 publications

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“…Our data, consistent with that from thymic CD301b + DC2 (Breed et al, 2022), indicates maturation and antigen presentation capacity as features strongly associated with DC2 expression of CD301b. While in certain contexts this state may primarily support Th2/Th17 differentiation, we observed concurrent upregulation of molecules associated with regulatory DC function, as has been observed in tumor-associated ‘mReg’ DC (Maier et al, 2020) and migratory DCs more generally (Nirschl et al, 2017).…”

Section: Discussionsupporting

confidence: 91%

“…We show in skin that expression of CD301b in DC2 strongly correlates with that of other phagocytic receptors and that these cells are efficient at bacterial uptake. Type 2 cytokines have been shown to promote CD301b + DC2 in the thymus (Breed et al, 2022) and CD11b lo DC in the skin (Mayer et al, 2021), but we found CD301b + DC2 cells still present in the skin of germ-free as well as Il13 -/- Il4r -/- neonates (data not shown). Thus, the specific pathways driving expression of CD301b and associated programs in skin DC2 remain to be determined.…”

Section: Discussioncontrasting

confidence: 54%

“…They can also optimize priming of naïve CD4 + T cells in lymph nodes by detaining these cells near the high endothelial venule for maximal antigen scanning (Tatsumi et al, 2021). In other models, they have been shown to support Th17 responses (Kim et al, 2018; Linehan et al, 2015) and to promote clonal deletion of thymic T cells (Breed et al, 2022). This suggests that the function of CD301b + DC2 is contextual, with our findings reflecting their contributions in a setting of early life tissue homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Other recent work examining DC2 in the thymus (Breed et al, 2022) has highlighted CD301b as marking a subset of DC2 with distinct functional capacity. Our results suggest that that specific functional capacity differs by tissue.…”

Section: Discussionmentioning

confidence: 99%

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Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

Weckel

Dhariwala

et al. 2022

Preprint

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

Weckel

Dhariwala

et al. 2022

Preprint

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“…The copyright holder for this preprint this version posted October 23, 2022. ; https://doi.org/10. 1101/2022.10.23.513409 doi: bioRxiv preprint the potential to impact the function of multiple cell types including CD8 T cells and dendritic cells (Breed et al, 2022;Verykokakis et al, 2010;Weinreich et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β promotes the postselection thymic development and peripheral function of interferon-γ-producing invariant natural killer T cells

Morgan

Frank

Greger

et al. 2022

Preprint

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Interferon-γ producing invariant natural killer T (iNKT1) cells are lipid reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell and thymic epithelial cell numbers or function. Here we show that a subset of thymic iNKT1 cells require transforming growth factor (TGF)-β induced signals for their development and for expression of residency associated adhesion receptors. Liver and spleen iNKT1 cells do not share this TGF-β gene signature but nonetheless TGF-β is required for optimal liver iNKT1 cell function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-β producing cells in the thymus.

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IL‐13 in dermal type‐2 dendritic cell specialization: From function to therapeutic targeting

2022

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Skin functions as a barrier protecting the host against physical, thermal, chemical changes as well as microbial insults. The skin is populated by several immune cell types that are crucial to host defense and to maintain self-tolerance as well as equilibrium with beneficial microbiota. Conventional dendritic cells (cDCs) are antigen-presenting cells that patrol the skin and all other nonlymphoid tissues for self or foreign antigens, and then migrate to draining lymph nodes to initiate T-cell responses. This review article describes recent developments on skin cDC specialization, focusing on the role of IL-13, a cytokine essential to allergic immune responses that is also secreted at steady state by type-2 innate lymphoid cells in healthy skin, and is required for dermal cDC differentiation. Furthermore, we contextualize how different therapeutics that block IL-13 signaling and were recently approved for the treatment of atopic dermatitis might affect cDCs in human skin.

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

Cited by 29 publications

References 62 publications

Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

Transforming growth factor-β promotes the postselection thymic development and peripheral function of interferon-γ-producing invariant natural killer T cells

IL‐13 in dermal type‐2 dendritic cell specialization: From function to therapeutic targeting

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