Lymphotoxin: from the physiology to the regeneration of the thymic function

Borelli, Alexia; Irla, Magali

doi:10.1038/s41418-021-00834-8

Cited by 29 publications

(21 citation statements)

References 102 publications

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“…The role of RANKL in the regeneration of the thymic microenvironment has been well characterized (82). Following thymic damage, RANKL induces up-regulation of lymphotoxina (LTa) which can bind to LTb receptor on thymic epithelial progenitor cells and TECs, and promote their regeneration (83).…”

Section: Ranklmentioning

confidence: 99%

“…The role of RANKL in the regeneration of the thymic microenvironment has been well characterized ( 82 ). Following thymic damage, RANKL induces up-regulation of lymphotoxin-α (LTα) which can bind to LTβ receptor on thymic epithelial progenitor cells and TECs, and promote their regeneration ( 83 ). Exogenous administration of recombinant RANKL boosts regeneration of TECs and improves T-cell progenitor homing and de novo thymopoiesis.…”

Section: Manipulating Thymic Function To Enhance Efficacy Of Cancer Immunotherapymentioning

confidence: 99%

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Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Cardinale¹,

Compagnucci²,

Locatelli³

et al. 2021

Front. Immunol.

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The capacity of T cells to recognize and mount an immune response against tumor antigens depends on the large diversity of the T-cell receptor (TCR) repertoire generated in the thymus during the process of T-cell development. However, this process is dramatically impaired by immunological insults, such as that caused by cytoreductive cancer therapies and infections, and by the physiological decline of thymic function with age. Defective thymic function and a skewed TCR repertoire can have significant clinical consequences. The presence of an adequate pool of T cells capable of recognizing specific tumor antigens is a prerequisite for the success of cancer immunotherapy using checkpoint blockade therapy. However, while this approach has improved the chances of survival of patients with different types of cancer, a large proportion of them do not respond. The limited response rate to checkpoint blockade therapy may be linked to a suboptimal TCR repertoire in cancer patients prior to therapy. Here, we focus on the role of the thymus in shaping the T-cell pool in health and disease, discuss how the TCR repertoire influences patients’ response to checkpoint blockade therapy and highlight approaches able to manipulate thymic function to enhance anti-tumor immunity.

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Section: Ranklmentioning

confidence: 99%

Section: Manipulating Thymic Function To Enhance Efficacy Of Cancer Immunotherapymentioning

confidence: 99%

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Cardinale¹,

Compagnucci²,

Locatelli³

et al. 2021

Front. Immunol.

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“…Among them, CCL19 (CCR7 ligand) is implicated in the medullary localization of thymocytes and the emigration of newly generated T cells ( Ueno et al, 2004 ); and CCL22 (CCR4 ligand) implicated in medullary entry and thymocyte/dendritic cell interactions ( Hu et al, 2015 ). Self-reactive CD4 + thymocytes also enhance CCL2 (CCR2 ligand) and CCL20 (CCR6 ligand) that promote the entry of peripheral dendritic cells and Foxp3 + regulatory T cells into the thymus ( Baba et al, 2009 ; Cédile et al, 2014 ; Cowan et al, 2018 ; Lopes et al, 2018 ; Borelli and Irla, 2021 ). mTEC-CD4 + thymocyte interactions thus induce key chemokines that regulate the trafficking of thymocytes and dendritic cells that participate in tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages

Lopes

Boucherit

Santamaria

et al. 2022

eLife

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Interactions of developing T cells with Aire+ medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEChi) are critical for the induction of central tolerance in the thymus. In turn, thymocytes regulate the cellularity of Aire+ mTEChi. However, it remains unknown whether thymocytes control the precursors of Aire+ mTEChi that are contained in mTEClo cells or other mTEClo subsets that have recently been delineated by single-cell transcriptomic analyses. Here, using three distinct transgenic mouse models, in which antigen presentation between mTECs and CD4+ thymocytes is perturbed, we show by high-throughput RNA-seq that self-reactive CD4+ thymocytes induce key transcriptional regulators in mTEClo and control the composition of mTEClo subsets, including Aire+ mTEChi precursors, post-Aire and tuft-like mTECs. Furthermore, these interactions upregulate the expression of tissue-restricted self-antigens, cytokines, chemokines, and adhesion molecules important for T-cell development. This gene activation program induced in mTEClo is combined with a global increase of the active H3K4me3 histone mark. Finally, we demonstrate that these self-reactive interactions between CD4+ thymocytes and mTECs critically prevent multiorgan autoimmunity. Our genome-wide study thus reveals that self-reactive CD4+ thymocytes control multiple unsuspected facets from immature stages of mTECs, which determines their heterogeneity.

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“…Lymphotoxin-α (LTα) is another member of TNF superfamily that was originally identified as a soluble factor secreted by lymphocytes having cytotoxic effects on tumor cells ( 71 , 72 ). Subsequent studies showed that, besides its soluble homotrimer (LTα3) form, LTα could associate with the transmembrane protein LTβ resulting in the membrane-bound heterotrimer LTα1β2 ( 73 ).…”

Section: Lymphotoxin-αmentioning

confidence: 99%

“…Besides activated T and B cells, LTα1β2 is also expressed by NKs and type 3 ILCs (ILC3). On the other hand, LTβR is mainly expressed by epithelial and endothelial cells among macrophages and DCs ( 72 ).…”

Section: Lymphotoxin-αmentioning

confidence: 99%

Signaling Crosstalks Drive Generation and Regeneration of the Thymus

et al. 2022

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Optimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting.

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Lymphotoxin: from the physiology to the regeneration of the thymic function

Cited by 29 publications

References 102 publications

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages

Signaling Crosstalks Drive Generation and Regeneration of the Thymus

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