Functional and metabolic dichotomy of murine γδ T cell subsets in cancer immunity

© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License.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.Our work is supported by “la Caixa” Foundation’s Health Research Program, project HR18-00069; PAC-PRECISE LISBOA-01-0145-FEDER-016394, co-funded by FEDER (POR Lisboa 2020) and Fundação para a Ciência e a Tecnologia (Portugal); and N.L. received an EMBO long term fellowship (ALTF 752–2018).info:eu-repo/semantics/publishedVersio

Induction de la tolérance centrale dans le thymus par le facteur de transcription Aire

L’établissement de la tolérance centrale thymique est un processus crucial pour prévenir le développement de pathologies auto-immunes. Les cellules épithéliales médullaires thymiques sont essentielles à ce processus via l’expression du facteur de transcription Aire. Celui-ci régule l’expression de nombreux antigènes spécifiques de tissus périphériques. Des mutations du gène codant pour Aire sont responsables du syndrome auto-immun appelé APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy). Cette revue traite du mode d’action de Aire au niveau moléculaire et épigénétique dans le contrôle de l’expression de ces auto-antigènes. Nous discutons également d’autres rôles, récemment décrits, de ce facteur de transcription dans l’induction de la tolérance centrale

γδ T cells in tissue physiology and surveillance

© Springer Nature Limited 2020γδ 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.Their work is supported by La Caixa Banking Foundation (project HR18-00069). J.C.R received a junior investigator contract from Fundação para a Ciência e Tecnologia (IF/00013/2014) and N.L. received an EMBO long-term fellowship (ALTF 752-2018).info:eu-repo/semantics/publishedVersio

Thymic crosstalk coordinates medulla organization and T-cell tolerance induction

International audienceThe 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

Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells

Autoreactive T cells are removed during their development in the thymus through the functions of medullary thymic epithelial cells (mTEC) and dendritic cells (DC), a process termed negative selection. Here the authors show that mTEC-T cell crosstalk and lymphotoxin α signalling are essential for the proper recruitment of DCs into the thymus

The Thymus-Specific Serine Protease TSSP/PRSS16 Is Crucial for the Antitumoral Role of CD4+ T Cells

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