Aire-dependent Production of XCL1 Mediates Medullary Accumulation of Thymic Dendritic Cells and Contributes to Regulatory T Cell Development

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2011 Feb 9

PMID 21300913

Citations 161

Authors

Yu Lei

Adiratna Mat Ripen

Naozumi Ishimaru

Izumi Ohigashi

Takashi Nagasawa

Lukas T Jeker

Michael R Bosl

Georg A Hollander

Yoshio Hayashi

Rene De Waal Malefyt

Takeshi Nitta

Yousuke Takahama

Affiliations

Soon will be listed here.

Abstract

Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire.

Citing Articles

The Thymus as a Mirror of the Body's Gene Expression.

Passos G, Genari A, Assis A, Monteleone-Cassiano A, Donadi E, Oliveira E Adv Exp Med Biol. 2025; 1471:247-268.

PMID: 40067590 DOI: 10.1007/978-3-031-77921-3_9.

Aire Mutations and Autoimmune Diseases.

Wolff A, Oftedal B Adv Exp Med Biol. 2025; 1471:223-246.

PMID: 40067589 DOI: 10.1007/978-3-031-77921-3_8.

Thymic Crosstalk: An Overview of the Complex Cellular Interactions that Control the Establishment of T-Cell Tolerance.

Irla M Adv Exp Med Biol. 2025; 1471:177-197.

PMID: 40067587 DOI: 10.1007/978-3-031-77921-3_6.

Intrathymic Cell Migration: Implications in Thymocyte Development and T Lymphocyte Repertoire Formation.

Mendes-da-Cruz D, Lemos J, Belorio E, Savino W Adv Exp Med Biol. 2025; 1471:139-175.

PMID: 40067586 DOI: 10.1007/978-3-031-77921-3_5.

The XCL1-XCR1 axis supports intestinal tissue residency and antitumor immunity.

Ferry A, Mempel K, Monell A, Reina-Campos M, Scharping N, Heeg M J Exp Med. 2025; 222(2.

PMID: 39841133 PMC: 11753173. DOI: 10.1084/jem.20240776.

References

Nitta T, Nitta S, Lei Y, Lipp M, Takahama Y . CCR7-mediated migration of developing thymocytes to the medulla is essential for negative selection to tissue-restricted antigens. Proc Natl Acad Sci U S A. 2009; 106(40):17129-33. PMC: 2761327. DOI: 10.1073/pnas.0906956106. View

Gallegos A, Bevan M . Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med. 2004; 200(8):1039-49. PMC: 2211843. DOI: 10.1084/jem.20041457. View

Mathis D, Benoist C . Aire. Annu Rev Immunol. 2009; 27:287-312. DOI: 10.1146/annurev.immunol.25.022106.141532. View

Dorner B, Dorner M, Zhou X, Opitz C, Mora A, Guttler S . Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity. 2009; 31(5):823-33. DOI: 10.1016/j.immuni.2009.08.027. View

Watanabe N, Wang Y, Lee H, Ito T, Wang Y, Cao W . Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 2005; 436(7054):1181-5. DOI: 10.1038/nature03886. View

Aschenbrenner K, DCruz L, Vollmann E, Hinterberger M, Emmerich J, Swee L . Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007; 8(4):351-8. DOI: 10.1038/ni1444. View

Mazzucchelli R, Hixon J, Spolski R, Chen X, Li W, Hall V . Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood. 2008; 112(8):3283-92. PMC: 2569178. DOI: 10.1182/blood-2008-02-137414. View

Moore N, Anderson G, McLoughlin D, Owen J, Jenkinson E . Differential expression of Mtv loci in MHC class II-positive thymic stromal cells. J Immunol. 1994; 152(10):4826-31. View

Hubert F, Kinkel S, Crewther P, Cannon P, Webster K, Link M . Aire-deficient C57BL/6 mice mimicking the common human 13-base pair deletion mutation present with only a mild autoimmune phenotype. J Immunol. 2009; 182(6):3902-18. DOI: 10.4049/jimmunol.0802124. View

10.

Piccirillo C, Shevach E . Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol. 2004; 16(2):81-8. DOI: 10.1016/j.smim.2003.12.003. View

11.

Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M . Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med. 2005; 202(1):33-45. PMC: 2212909. DOI: 10.1084/jem.20050471. View

12.

Flotte T, Springer T, Thorbecke G . Dendritic cell and macrophage staining by monoclonal antibodies in tissue sections and epidermal sheets. Am J Pathol. 1983; 111(1):112-24. PMC: 1916197. View

13.

Dorner B, Scheffold A, Rolph M, Huser M, Kaufmann S, Radbruch A . MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci U S A. 2002; 99(9):6181-6. PMC: 122923. DOI: 10.1073/pnas.092141999. View

14.

Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, Hayashi Y . Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol. 2005; 174(4):1862-70. DOI: 10.4049/jimmunol.174.4.1862. View

15.

Koble C, Kyewski B . The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med. 2009; 206(7):1505-13. PMC: 2715082. DOI: 10.1084/jem.20082449. View

16.

Barnden M, Allison J, Heath W, Carbone F . Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol. 1998; 76(1):34-40. DOI: 10.1046/j.1440-1711.1998.00709.x. View

17.

Barclay A, Mayrhofer G . Bone marrow origin of Ia-positive cells in the medulla rat thymus. J Exp Med. 1981; 153(6):1666-71. PMC: 2186196. DOI: 10.1084/jem.153.6.1666. View

18.

Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E . CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999; 99(1):23-33. DOI: 10.1016/s0092-8674(00)80059-8. View

19.

Curotto de Lafaille M, Lafaille J . Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity. 2009; 30(5):626-35. DOI: 10.1016/j.immuni.2009.05.002. View

20.

Gillard G, Dooley J, Erickson M, Peltonen L, Farr A . Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J Immunol. 2007; 178(5):3007-15. DOI: 10.4049/jimmunol.178.5.3007. View