Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla

Irla, Magali; Guerri, Lucia; Guenot, J; Sergé, Arnauld; Lantz, Olivier; Liston, Adrian; Imhof, Beat A.; Palmer, Ed; Reith, Walter

doi:10.1371/journal.pone.0052591

Cited by 30 publications

(37 citation statements)

References 47 publications

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“…In particular, CD40L, RANKL and LTαβ have all been shown to be upregulated on SP thymocytes relative to DN and DP thymocytes (6); and mice lacking RANK-RANKL, LTαβ-LTβR or CD40-CD40L interactions have mTEC compartment defects of varying severities (6, 25, 38, 40, 41). Consistent with recent reports (37, 52), we found that expression of LTαβ on CD4 SP thymocytes is decreased in the absence of CD28-CD80/86 interactions. Our finding that LTβR/CD40 combined KO mice have a more profound mTEC defect than either the LTβR or CD40 single KOs suggests that CD28-CD80/86 cooperates with CD40-CD40L interactions to promote mTEC development, in part via increased LTαβ production by CD4 SP thymocytes.…”

Section: Discussionsupporting

confidence: 93%

Thymic Medullary Epithelium and Thymocyte Self-Tolerance Require Cooperation between CD28–CD80/86 and CD40–CD40L Costimulatory Pathways

Williams

Zhang

Jeon

et al. 2014

The Journal of Immunology

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A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC) and mTEC development in turn requires signals from mature single positive (SP) thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTα, LTβ and RANK in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of SP thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 KO mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development.

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Section: Discussionsupporting

confidence: 93%

Thymic Medullary Epithelium and Thymocyte Self-Tolerance Require Cooperation between CD28–CD80/86 and CD40–CD40L Costimulatory Pathways

Williams

Zhang

Jeon

et al. 2014

The Journal of Immunology

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“…Our findings are consistent with the recent report that combined stimulation of 2-dGUO-treated thymic lobes with agonist anti-LTβR antibody and CD40L synergized in the in vitro induction of mTECs (28), importantly extending these findings by demonstrating that LTβR and CD40L pathways, in fact, interact cooperatively during in vivo thymic development as evidenced by the severe reduction in mTEC numbers we observed in mice deficient in both pathways.…”

Section: Discussionsupporting

confidence: 93%

TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development

Jenkinson

Williams

Jeon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Induction of self-tolerance in developing T cells depends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals from single-positive (SP) thymocytes. Thus, the absence of SP thymocytes in Tcra −/− mice results in a profound deficiency in mTECs. Here, we have probed the mechanism that underlies this requirement for cross-talk with thymocytes in medullary development. Previous studies have implicated nonclassical NF-κB as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKKα, critical components of this pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology. We therefore assessed the effect of selective deletion in TEC of TNF receptor-associated factor 3 (TRAF3), an inhibitor of nonclassical NF-κB signaling. Deletion of TRAF3 in thymic epithelial cells allowed RelB-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes. Thus, mTEC development can occur in the absence of cross-talk with SP thymocytes, and signals provided by SP T cells are needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical NF-κB. We further observed that TRAF3 deletion is also capable of overcoming all requirements for LTβR and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the requirement for RANKL, indicating a role for RANKL that is distinct from the signals provided by SP thymocytes. We conclude that TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells and costimulation-mediated cross-talk in generation of the medullary compartment.A major role of the thymus is the generation of a functional T-cell repertoire that is broadly responsive to foreign antigens but is self-tolerant. Through their role in exposing developing thymocytes to a spectrum of self-antigens, the stromal cells of the thymus are integral to this tolerization. Of particular importance in this process are the epithelial cells comprising the thymic medulla, the region of the thymus where thymocytes selected into the CD4 and CD8 single-positive (SP) lineages reside before emigrating to the periphery (reviewed in refs. 1-3). The importance of thymic medullary epithelial cells (mTECs) in the maintenance of self-tolerance is illustrated by the destructive autoreactivity that results from disruption of mTEC development (reviewed in ref. 4).Just as mTECs have a central role in shaping the developing T-cell repertoire, thymocytes, in turn, are vital to the development and maintenance of the mTEC compartment, a bidirectional interaction that has been termed cross-talk (5-7). A number of recent reports have characterized the CD4 SP thymocyte-stromal cell interactions that are critical for mTEC development (5-11). However, the mechanism that enforces the requirement for SP thymocytes in mTEC development has not been fully identified.We therefore addressed the signaling requirements that mediate the c...

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“…This suggests that reduced thymic cDC cellularity in NOD.TCRα −/− mice is due to a developmental defect in the absence of SP, which may be especially relevant for intrathymically-derived CD8α + cDC. It is possible that mTEC, which are also reduced in TCRα −/− mice (28, 29, 32), contribute to thymic cDC cellularity and maturation. mTEC may provide a niche through production of chemokines such as XCL1 and CCL8 or other factors that regulate thymic cDC localization, recruitment, and/or maturation (17, 21, 33).…”

Section: Resultsmentioning

confidence: 99%

“…mTEC may provide a niche through production of chemokines such as XCL1 and CCL8 or other factors that regulate thymic cDC localization, recruitment, and/or maturation (17, 21, 33). However, thymic DC numbers are normal in β2M- or MHC II-deficient mice, the latter exhibiting a reduced mature mTEC pool (29, 32). These findings illustrate 2 key points: 1) either SPCD4 or SPCD8 are sufficient to sustain DC homeostasis, consistent with our findings in peptide-treated BDC2.5/TCRα −/− and CL4.…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Antigen-Specific Thymocyte Feedback Regulates Homeostatic Thymic Conventional Dendritic Cell Maturation

Spidale

Wang

Tisch

2014

The Journal of Immunology

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Thymic dendritic cells (DC) mediate self-tolerance by presenting self-peptides to and depleting autoreactive thymocytes. Despite a significant role in negative selection, the events regulating thymic DC maturation and function under steady-state conditions are poorly understood. We report that crosstalk with thymocytes regulates thymic conventional DC (cDC) numbers, phenotype, and function. In mice lacking TCR-expressing thymocytes, thymic cDC were reduced and exhibited a less mature phenotype. Furthermore, thymic cDC in TCR transgenic mice lacking cognate antigen expression in the thymus were also immature; notably, however, thymic cDC maturation was reestablished by an Ag-specific cognate interaction with CD4+ or CD8+ single-positive thymocytes (SP). Blockade of CD40 ligand during Ag-specific interactions with CD4SP but not CD8SP limited the effect on cDC maturation. Together, these novel findings demonstrate that homeostatic maturation and function of thymic cDC is regulated by feedback delivered by CD4SP and CD8SP via distinct mechanisms during a cognate Ag-specific interaction.

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Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla

Cited by 30 publications

References 47 publications

Thymic Medullary Epithelium and Thymocyte Self-Tolerance Require Cooperation between CD28–CD80/86 and CD40–CD40L Costimulatory Pathways

Thymic Medullary Epithelium and Thymocyte Self-Tolerance Require Cooperation between CD28–CD80/86 and CD40–CD40L Costimulatory Pathways

TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development

Cutting Edge: Antigen-Specific Thymocyte Feedback Regulates Homeostatic Thymic Conventional Dendritic Cell Maturation

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