Transitional Dendritic Cells Are Distinct from Conventional DC2 Precursors and Mediate Proinflammatory Antiviral Responses

Overview

Journal Nat Immunol

Date 2023 Jul 6

PMID 37414907

Authors

Fernando Bandeira Sulczewski

Raul A Maqueda-Alfaro

Marcela Alcantara-Hernandez

Oriana A Perez

Sanjana Saravanan

Tae Jin Yun

David Seong

Rebeca Arroyo Hornero

Hayley M Raquer-McKay

Eduardo Esteva

Zachary R Lanzar

Rebecca A Leylek

Nicholas M Adams

Annesa Das

Adeeb H Rahman

Andres Gottfried-Blackmore

Boris Reizis

Juliana Idoyaga

Affiliations

Soon will be listed here.

Abstract

High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the origin and relationship of tDCs to other DC subsets has been unclear. Here we show that tDCs are distinct from other well-characterized DCs and conventional DC precursors (pre-cDCs). We demonstrate that tDCs originate from bone marrow progenitors shared with plasmacytoid DCs (pDCs). In the periphery, tDCs contribute to the pool of ESAM type 2 DCs (DC2s), and these DC2s have pDC-related developmental features. Different from pre-cDCs, tDCs have less turnover, capture antigen, respond to stimuli and activate antigen-specific naïve T cells, all characteristics of differentiated DCs. Different from pDCs, viral sensing by tDCs results in IL-1β secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDCs are a distinct pDC-related subset with a DC2 differentiation potential and unique proinflammatory function during viral infections.

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References

Persson E, Uronen-Hansson H, Semmrich M, Rivollier A, Hagerbrand K, Marsal J . IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity. 2013; 38(5):958-69. DOI: 10.1016/j.immuni.2013.03.009. View

Siegemund S, Shepherd J, Xiao C, Sauer K . hCD2-iCre and Vav-iCre mediated gene recombination patterns in murine hematopoietic cells. PLoS One. 2015; 10(4):e0124661. PMC: 4401753. DOI: 10.1371/journal.pone.0124661. View

Kaitani A, Izawa K, Maehara A, Isobe M, Takamori A, Matsukawa T . Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8)/CLM-6 is an FcRγ-coupled receptor selectively expressed in mouse tissue plasmacytoid dendritic cells. Sci Rep. 2018; 8(1):8259. PMC: 5974347. DOI: 10.1038/s41598-018-25646-8. View

Bourdely P, Anselmi G, Vaivode K, Ramos R, Missolo-Koussou Y, Hidalgo S . Transcriptional and Functional Analysis of CD1c Human Dendritic Cells Identifies a CD163 Subset Priming CD8CD103 T Cells. Immunity. 2020; 53(2):335-352.e8. PMC: 7445430. DOI: 10.1016/j.immuni.2020.06.002. View

Papaioannou N, Salei N, Rambichler S, Ravi K, Popovic J, Kuntzel V . Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice. Nat Commun. 2021; 12(1):464. PMC: 7815729. DOI: 10.1038/s41467-020-20659-2. View

Cytlak U, Resteu A, Pagan S, Green K, Milne P, Maisuria S . Differential IRF8 Transcription Factor Requirement Defines Two Pathways of Dendritic Cell Development in Humans. Immunity. 2020; 53(2):353-370.e8. PMC: 7447982. DOI: 10.1016/j.immuni.2020.07.003. View

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

Lutz K, Musumeci A, Sie C, Dursun E, Winheim E, Bagnoli J . Ly6DSiglec-H precursors contribute to conventional dendritic cells via a Zbtb46Ly6D intermediary stage. Nat Commun. 2022; 13(1):3456. PMC: 9200809. DOI: 10.1038/s41467-022-31054-4. View

10.

Schlitzer A, Sivakamasundari V, Chen J, Sumatoh H, Schreuder J, Lum J . Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow. Nat Immunol. 2015; 16(7):718-28. DOI: 10.1038/ni.3200. View

11.

Cabeza-Cabrerizo M, Minutti C, Pereira da Costa M, Cardoso A, Jenkins R, Kulikauskaite J . Recruitment of dendritic cell progenitors to foci of influenza A virus infection sustains immunity. Sci Immunol. 2021; 6(65):eabi9331. PMC: 7612017. DOI: 10.1126/sciimmunol.abi9331. View

12.

Yun T, Igarashi S, Zhao H, Perez O, Pereira M, Zorn E . Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells. Sci Immunol. 2021; 6(58). PMC: 8221820. DOI: 10.1126/sciimmunol.abc7302. View

13.

Lewis K, Caton M, Bogunovic M, Greter M, Grajkowska L, Ng D . Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity. 2011; 35(5):780-91. PMC: 3225703. DOI: 10.1016/j.immuni.2011.08.013. View

14.

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

15.

See P, Dutertre C, Chen J, Gunther P, McGovern N, Irac S . Mapping the human DC lineage through the integration of high-dimensional techniques. Science. 2017; 356(6342). PMC: 7611082. DOI: 10.1126/science.aag3009. View

16.

Dutertre C, Becht E, Irac S, Khalilnezhad A, Narang V, Khalilnezhad S . Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells. Immunity. 2019; 51(3):573-589.e8. DOI: 10.1016/j.immuni.2019.08.008. View

17.

Bergen V, Lange M, Peidli S, Wolf F, Theis F . Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol. 2020; 38(12):1408-1414. DOI: 10.1038/s41587-020-0591-3. View

18.

Spitzer M, Gherardini P, Fragiadakis G, Bhattacharya N, Yuan R, Hotson A . IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science. 2015; 349(6244):1259425. PMC: 4537647. DOI: 10.1126/science.1259425. View

19.

Cervantes-Barragan L, Lewis K, Firner S, Thiel V, Hugues S, Reith W . Plasmacytoid dendritic cells control T-cell response to chronic viral infection. Proc Natl Acad Sci U S A. 2012; 109(8):3012-7. PMC: 3286988. DOI: 10.1073/pnas.1117359109. View

20.

Tussiwand R, Everts B, Grajales-Reyes G, Kretzer N, Iwata A, Bagaitkar J . Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity. 2015; 42(5):916-28. PMC: 4447135. DOI: 10.1016/j.immuni.2015.04.017. View