Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27–CD70 pathway

Coquet, Jonathan M.; Ribot, Julie C.; Bąbała, Nikolina; Middendorp, Sabine; Horst, G.; Xiao, Yanling; Neves, Joana F.; Fonseca-Pereira, Diogo; Jacobs, Heinz; Pennington, Daniel J.; Silva‐Santos, Bruno; Borst, Jannie

doi:10.1084/jem.20112061

Cited by 136 publications

(140 citation statements)

References 76 publications

(124 reference statements)

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“…Therefore, CD27 signaling either improved the function of or enhanced the exhaustion and death of effector T cells, depending on the strength, duration, and timing of the agonistic stimulation (16,17,35,37). Additionally, slower tumor growth in CD27 2/2 mice due to diminished T reg numbers was reported, supporting the role of CD70-CD27 interaction in the generation and survival of T reg (38,39).…”

mentioning

confidence: 78%

“…An additional concern arises from studies reporting that CD27 signaling favors T reg development or survival and that the absence of CD27 in CD27 2/2 mice leads to slower tumor growth compared with wild-type mice (38,39). It has also been reported that T reg from CD70 2/2 mice were reduced and not as efficient at suppressing CD4 Th cell proliferation compared with T reg from wild-type mice, suggesting a role for the CD70-CD27 interaction in maintaining T reg survival and function (59).…”

Section: Discussionmentioning

confidence: 99%

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CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

Wasiuk

Testa

Weidlick

et al. 2017

The Journal of Immunology

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CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcγRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcγRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.

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mentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

Wasiuk

Testa

Weidlick

et al. 2017

The Journal of Immunology

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“…However, our data from in vitro culture of F5 thymocytes suggest the Tnfrsf ligands such as TNF and CD70 may be implicated. There is already evidence to suggest these ligands may be present in the thymus because TNF mRNA can be detected in dendritic cells ex vivo (32), and CD70 is already implicated in development of regulatory T cells in the thymus (33). Future studies should address whether these ligands alone are sufficient for induction of Il7r expression or whether other NF-κB-activating receptors may be involved.…”

Section: Discussionmentioning

confidence: 99%

NF-κB signaling mediates homeostatic maturation of new T cells

Silva

Cornish

Ley

et al. 2014

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

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Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. IL-7 receptor α ( IL-7Rα) expression is subject to developmental regulation and new T cells induce expression as they leave the thymus, which is essential for their long-term survival. It is not understood how this expression is regulated. Here, we identify a role for the Nuclear Factor κ-B (NF-κB) signaling pathway in controlling expression of IL-7Rα in new T cells. Perturbations to NF-κB signaling, either by deletion of Inhibitor of Kappa-B Kinase-2 (IKK2) or by inhibiting Rel dimer activity, prevented normal IL-7Rα expression in new T cells. Defective IL-7Rα expression resulted in impaired survival and homeostatic cell division responses by T cells that could be attributed to their failure to express IL-7Rα normally. Surprisingly, NF-κB signaling was only required transiently in new T cells to allow their normal expression of IL-7Rα, because IKK2 deletion in mature T cells had no effect on IL-7Rα expression or their normal homeostatic responsiveness. Therefore, we identify a developmental function for NF-κB signaling in the homeostatic maturation of new T cells, by regulating IL-7Rα expression. M aintaining T lymphocytes in sufficient numbers and at an appropriate composition of differentiation states and subtypes is essential for effective immunity. The immune system has evolved a number of homeostatic mechanisms to ensure the size and composition of the T-cell compartment remains remarkably stable over time. The cytokine interleukin (IL)-7 plays a central role in regulating homeostasis of the T-cell compartment. It is essential for normal development of αβ and γδ T cells in the thymus and provides vital survival signals for both naive and memory T cells in the periphery (1). IL-7 is produced by stromal cell components in bone marrow, thymus, and in peripheral lymphoid compartments (2), and there is extensive evidence that production of IL-7 is a key factor that determines and limits the overall size of the peripheral T-cell compartment (3, 4). The receptor for IL-7 is a member of the common-gamma chain (γc) family of cytokine receptors and consists of a heterodimeric complex of IL-7Rα and γc (5).In T cells, IL-7 signaling is primarily regulated at the level of IL-7Rα expression. During T-cell development in the thymus, expression of IL-7Rα by thymocytes is subject to dynamic developmental regulation. IL-7Rα is essential for survival and development of CD4 CD8 double negative (DN) thymocytes (6). Expression is lost at the CD4 CD8 double positive (DP) stage, ensuring that onward development of DP thymocytes is restricted to those that successfully undergo positive selection (7). Immediately following selection, however, IL-7Rα is immediately reexpressed and recent studies suggest that the strength of T-cell receptor (TCR)-mediated positive selection signaling determines the extent of reexpression by SP thymocytes (8). Following egress from the thymus, new T cells continue to mature as recent ...

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“…7B), possibly accounting for the upregulation of CD27 on CD4SP and CD8SP thymocytes in aly/aly mice. In this context, a recent report suggesting that mTECs, together with thymic DCs, promote Treg production via the CD27-CD70 pathway merits attention (44). The authors suggested that the CD27-CD70 pathway rescues developing Tregs from apoptosis.…”

Section: Foxp3mentioning

confidence: 99%

NF-κB–Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells

Mouri

Nishijima

Kawano

et al. 2014

The Journal of Immunology

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Essential roles of NF-κB–inducing kinase (NIK) for the development of medullary thymic epithelial cells (mTECs) and regulatory T cells have been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice). However, the exact mechanisms underlying the defect in thymic cross-talk leading to the breakdown of self-tolerance in aly mice remain elusive. In this study, we demonstrated that production of regulatory T cells and the final maturation process of positively selected conventional αβ T cells are impaired in aly mice, partly because of a lack of mature mTECs. Of note, numbers of thymic dendritic cells and their expression of costimulatory molecules were also affected in aly mice in a thymic stroma–dependent manner. The results suggest a pivotal role of NIK in the thymic stroma in establishing self-tolerance by orchestrating cross-talk between mTECs and dendritic cells as well as thymocytes. In addition, we showed that negative selection was impaired in aly mice as a result of the stromal defect, which accounts for the development of organ-specific autoimmunity through a lack of normal NIK.

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Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27–CD70 pathway

Abstract: CD27–CD70 signals are required for optimal development of natural regulatory T cells from the thymus.

Cited by 136 publications

References 76 publications

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

NF-κB signaling mediates homeostatic maturation of new T cells

NF-κB–Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells

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