γδ T cells are a unique T cell subpopulation that are rare in secondary lymphoid organs but enriched in many peripheral tissues, such as the skin, intestines and lungs. By rapidly producing large ...amounts of cytokines, γδ T cells make key contributions to immune responses in these tissues. In addition to their immune surveillance activities, recent reports have unravelled exciting new roles for γδ T cells in steady-state tissue physiology, with functions ranging from the regulation of thermogenesis in adipose tissue to the control of neuronal synaptic plasticity in the central nervous system. Here, we review the roles of γδ T cells in tissue homeostasis and in surveillance of infection, aiming to illustrate their major impact on tissue integrity, tissue repair and immune protection.
γδ T cells can display a plethora of immune functions, but recent studies have highlighted their importance, in multiple disease models, as sources of the pro‐inflammatory cytokines, IL‐17A (IL‐17), ...and IFN‐γ. These are produced by distinct murine effector γδ T cell subsets that diverge during thymic γδ T cell development. Among the multiple roles these subsets play in peripheral tissues, a striking dichotomy has emerged at tumor sites: whereas IFN‐γ+ γδ T cells inhibit tumor cell growth, IL‐17+ γδ T cells promote tumor progression and metastasis formation. In this review, we discuss the main lines of evidence, mostly from preclinical studies in mouse models, for this functional dichotomy in cancer immunity. We further highlight very recent advances in our understanding how metabolic sources and pathways can impact on the balance between IFN‐γ+ and IL‐17+ γδ T cells in the tumor microenvironment, which opens a new exciting avenue to explore toward the application of γδ T cells in cancer immunotherapy.
γδ T cell subsets have opposite roles in cancer immunity: whereas IFN‐γ+ γδ T cells inhibit tumor cell growth, IL‐17+ γδ T cells promote tumor progression and metastasis formation. Furthermore, metabolic sources and pathways can impact on the γδ T cell subset balance in the tumor microenvironment. Manipulating γδ metabolism may pave the way toward the development of novel immunotherapies.
Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral ...self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4
thymocyte crosstalk regulates the thymus homing of SHPS-1
conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders.
The thymus ensures the generation of a functional and highly diverse T-cell repertoire. The thymic medulla, which is mainly composed of medullary thymic epithelial cells (mTECs) and dendritic cells ...(DCs), provides a specialized microenvironment dedicated to the establishment of T-cell tolerance. mTECs play a privileged role in this pivotal process by their unique capacity to express a broad range of peripheral self-antigens that are presented to developing T cells. Reciprocally, developing T cells control mTEC differentiation and organization. These bidirectional interactions are commonly referred to as thymic crosstalk. This review focuses on the relative contributions of mTEC and DC subsets to the deletion of autoreactive T cells and the generation of natural regulatory T cells. We also summarize current knowledge regarding how hematopoietic cells conversely control the composition and complex three-dimensional organization of the thymic medulla.
In cancer, immune cells can play conflicting roles, either protective, by elimination of tumor cells during immune surveillance, or detrimental, by promoting carcinogenesis during inflammation. We ...report here that the thymus-specific serine protease (TSSP), which is involved in CD4+ T cell maturation in the thymus, exerts a tumor suppressor activity. Mice genetically deficient for TSSP are highly prone to spontaneous cancer development. The absence of TSSP also increases the rate of induced colitis-associated colorectal (CAC) tumor formation, through exacerbated colon inflammation. Adoptive transfer of T cells in various combinations (CD4+ and CD8+ from wild-type and/or knockout mice) into T cell-deficient mice showed that the TSSP-deficient CD4+ T cell compartment promotes tumor development, associated with high levels of the cytokine IL-17A. Inhibition of IL-17A during CAC tumor formation prevents the increased carcinogenesis and colic immune disequilibrium observed in TSSP-deficient mice. Therefore, our data demonstrate that antitumoral immune surveillance requires thymic TSSP-driven production of CD4+ T cells contributing to inflammatory balance.
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•TSSP is an important protease for intrathymic selection of CD4+ T cells•Absence of TSSP favors both spontaneous and inflammation-induced tumor development•TSSP-dependent maturation of CD4+ T cells in the thymus is required for tumor suppression•TSSP is a thymic protease with tumor suppressor activity
The thymus-specific serine protease (TSSP) is involved in CD4+ T lymphocyte selection in the thymus. Brisson et al. now reveal a function of TSSP in the prevention of cancer. Both spontaneous and inflammation-associated tumor development is promoted in TSSP-deficient mice through the production of an altered CD4+ T cell compartment.
Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T‐cell immunodeficiency. Understanding the ...mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, we show that RANK ligand (RANKL) is upregulated in CD4+ thymocytes and lymphoid tissue inducer (LTi) cells during the early phase of thymic regeneration. Importantly, whereas RANKL neutralization alters TEC recovery after irradiation, ex vivo RANKL administration during BMT boosts the regeneration of TEC subsets including thymic epithelial progenitor‐enriched cells, thymus homing of lymphoid progenitors, and de novo thymopoiesis. RANKL increases specifically in LTi cells, lymphotoxin α, which is critical for thymic regeneration. RANKL treatment, dependent on lymphotoxin α, is beneficial upon BMT in young and aged individuals. This study thus indicates that RANKL may be clinically useful to improve T‐cell function recovery after BMT by controlling multiple facets of thymic regeneration.
Synopsis
Ex vivo RANKL administration boosts thymic epithelial cell regeneration and ameliorates T‐cell reconstitution by enhancing thymus homing upon bone marrow transplant (BMT). These effects are beneficial to both young and aged individuals and mediated by LTα expression in lymphoid tissue inducer (LTi) cells.
RANKL is upregulated in CD4+ thymocytes and LTi cells upon thymic injury.
RANKL induces LTα upregulation specifically in thymic LTi cells after total body irradiation.
Ex vivo RANKL administration boosts the regeneration of thymic epithelial cells and T‐cell reconstitution in a LTα‐dependent manner.
RANKL treatment ameliorates thymic recovery in young and aged individuals after BMT.
Ex vivo RANKL administration boosts thymic epithelial cell regeneration and ameliorates T‐cell reconstitution by enhancing thymus homing upon bone marrow transplant (BMT). These effects are beneficial to both young and aged individuals and mediated by LTα expression in lymphoid tissue inducer (LTi) cells.
Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or ...interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ
γδ T cells were almost exclusively dependent on glycolysis, IL-17
γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17
γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ
γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.
Interactions of developing T cells with Aire
medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEC
) are critical for the induction of central tolerance in the thymus. In ...turn, thymocytes regulate the cellularity of Aire
mTEC
. However, it remains unknown whether thymocytes control the precursors of Aire
mTEC
that are contained in mTEC
cells or other mTEC
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 mTEC
and control the composition of mTEC
subsets, including Aire
mTEC
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 mTEC
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.
Natural killer cells can drive spreading cancer cells to enter a state of dormancy. That finding, together with the discovery of a pathway that hinders this antitumour function, could spur the ...development of new treatments.
Dans le thymus, la médulla constitue un compartiment essentiel pour la délétion clonale et la génération de lymphocytes T régulateurs (Tregs). En retour, les thymocytes CD4+ contrôlent le ...développement des cellules épithéliales thymiques médullaires (CETms). Ces échanges bidirectionnels sont appelés « crosstalk ». Il a été montré que durant le crosstalk, les thymocytes CD4+ surexpriment la lymphotoxine $alpha$ (LT$alpha$) qui contrôle l’organisation de la médulla. Durant ma thèse, j’ai étudié le rôle de la LT$alpha$ dans la : (1) régénération thymique après greffe de moelle osseuse (GMO), (2) migration des cellules présentatrices d’antigènes (Ag) (CPAs) dans le thymus et (3) fonction suppressive des Tregs. Le projet 1 a montré que la LT$alpha$, régulée par RANKL, est surexprimée dans les cellules inductrices de tissus lymphoïdes (LTi) après GMO et est critique pour la régénération du thymus. Par ailleurs, le projet 2 a montré que la LT$alpha$ limite la migration des CPAs dans le thymus pour contrôler la délétion clonale. De façon intéressante, les Tregs expriment fortement la LT$alpha$. Le projet 3 a montré que les Tregs Lta-/- présentent une signature hyper-suppressive et que le transfert de ces cellules protège de l'inflammation intestinale et atténue le développement de l’auto-immunité. Enfin, le dernier projet a démontré que les thymocytes CD4+ via les interactions Ag-spécifiques induisent le développement et la fonction des CETms. En absence de ces interactions, les cellules T sont auto-réactives et induisent de l’auto-immunité, indiquant qu’elles sont essentielles à l’induction de la tolérance centrale.
In the thymus, medulla constitutes an essential compartment for clonal deletion and the generation of regulatory T lymphocytes (Tregs). Reciprocally, CD4+ thymocytes control the development of medullary thymic epithelial cells (mTECs). These bi-directional interactions are referred to as "crosstalk". It has been shown that this crosstalk induces the expression of lymphotoxin $alpha$ (LT$alpha$) in autoreactive CD4+ thymocytes, which controls the medulla organization. During my thesis, I studied the role of LT$alpha$ in: (1) thymic regeneration after bone marrow transplantation (BMT), (2) migration of antigen (Ag) presenting cells (APCs) in the thymus and (3) suppressive functions of Tregs. Project 1 has shown that LT$alpha$, regulated by RANKL, is overexpressed in lymphoid tissue inducer cells (LTi) after BMT and is critical for thymic regeneration. Furthermore, projet 2 has demonstrated that LT⍺ limits the migration of thymic APCs to fine-tune clonal deletion. Interestingly, Tregs strongly express LTα. Project 3 has demonstrated that Lta-/- Tregs exhibit a highly suppressive signature and that the transfer of these cells protects from intestinal inflammation and attenuates the development of autoimmunity. Finally, the last project has revealed that CD4+ thymocytes via Ag-specific interactions induce the development and function of mTECs. In absence of these interactions, T cells are autoreactive and induce autoimmunity, indicating that they are essential for the induction of T-cell tolerance.
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