Journal Club
01
Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion
Deepali V. Sawant, Hiroshi Yano, MariaChikina, Qianxia Zhang , Mengting Liao,Chang Liu, Derrick J. Callahan, Zhe Sun,Tao Sun, Tracy Tabib, Arjun Pennathur, David B. Corry, James D. Luketich,Robert Lafyatis, Wei Chen , Amanda C. Poholek, Tullia C. Bruno, Creg J. Workman and Dario A. A. Vignali *
Nature Immunology (2019)
This paper focused on the role of Tregs in the tumor microenvironment. Previous papers described of the various regulatory T (TReg)-cell mechanisms centred around four basic modes of action: a| Inhibitory cytokines include interleukin-10 (IL-10), IL-35 and transforming growth factor-β (TGFβ). b| Cytolysis includes granzyme-A- and granzyme-B-dependent and perforin-dependent killing mechanisms. c| Metabolic disruption. d| Targeting dendritic cells (DCs) includes mechanisms that modulate DC maturation and/or function. Although Treg cells and suppressive cytokines have been linked to T cell exhaustion in chronic settings, the molecular mechanisms and the relative contribution of Treg cell-derived suppressive cytokines underlying Treg cell-induced exhaustion remain obscure. In this paper, the authors pay their attention to the cytokines IL-10 and IL-35 productive Tregs and reveal the mechanisms of Tregs induced CD8 T cell exhaustion. Firstly, they found that segregated expression of IL-10 and Ebi3 by Treg cells in various lymphoid and nonlymphoid organs, with minimal co-expression. Then they performed RNA-Seq and single cell seq, results showed that IL-10+ and Ebi3+ Treg cells exhibited comparable transcriptomic signatures and there was no bias in TCR Vβ-gene usage or CDR3-length in these two subsets Tregs. To assess the functional impact of IL-10- and IL-35-producing Treg cell subpopulations on the TME, they compared the growth rate of three transplantable tumor models; B16 and BrafPten (clone 24) melanoma models and EL4 thymoma in mice and analyzed the impact of inhibitory cytokine-driven multi-inhibitory receptor induction on CD8+ T cell differentiation as well as other cell types in the TME. To investigate whether IL-10 and IL-35 were directly impacting CD8+ T cells in the TME or if this regulation required an inter-mediator accessory cell, they used Rag1–/–reconstitution model and confirmed that reconstitution with IL-35receptor-deficient or IL-10 receptor-deficientCD8+ T cells recapitulated the reduced B16 tumor growth observed in mice with Treg cells that cannot make IL-35 and IL-10, respectively. They then probed the mechanistic underpinnings of IL-10 and IL-35-driven multi-inhibitory receptor upregulation to assess if these Treg cell subpopulations used similar or distinct downstream mechanisms to drive T cell dysfunction. They found that Treg cell-derived IL-10 and IL-35 regulate CD8+TILs through BLIMP1-inhibitory receptor axis and confirmed the direct and cooperative regulation of BLIMP1-inhibitory receptor axis in CD8+ TILs by IL-10and IL-35.
This paper provided new insight into how the Tregs regulate the CD8 T cells exhaustion and suggested a new strategy for cancer treatment.
https://doi.org/10.1038/s41590-019-0346-9
02
c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells
Leona Gabryšová, Marisol Alvarez-Martinez, ... Greg Elgar, Mark Wilson, James Briscoe, Vicki Metzis, JeanLanghorne, Nicholas M. Luscombe & Anne O’Garra et al.
Nature Immunology (2018)
CD4 T helper (TH) lymphocytes are essential regulators of immune responses and inflammatory diseases. After being activated by professional antigen-presenting cells (APCs), TH cells differentiate into effector cells specialized in cytokine secretion and function. Effector TH cells have been classified as type 1 (TH1) , type 2 (TH2), TH17 and Treg based on their cytokine expression profiles and immune regulatory function. Subsets of CD4+ helper T cells, including TH1, TH2 and TH17 cells, are critical for the eradication of specific pathogens, but if they are uncontrolled, they can contribute to immunopathology, either during infection or during immune system–mediated diseases. There are different mechanisms that keep the homeostasis of immune system including production of the anti-inflammatory cytokine IL-10 and CD4+regulatory T cells (Treg cells). Many TFs have been shown to modulate Il10 expression, including c-Maf and although c-Maf has been shown to positively regulate Il10 expression in vitro, its effects on Il10 and global gene expression across different immune responses in vivo are unknown. In this paper, the authors study the regulatory role of c-Maf in CD4 T cells in vivo. Firstly , the check the expression of Maf and that of Il10 correlate in all helper T cell and Treg cell subsets. Results showed that c-Maf might function as a common regulator of IL-10 in CD4+ T cells regardless of the T cell subset. Then they detected the role of c-Maf in different disease model and demonstrated that c-Maf deficiency in CD4+ T cells affects susceptibility to disease in a context-specific manner. To better understand the disease-specific effects of the deletion of Maf, they performed RNA-seq analysis of purified CD4+ T cells isolated from different organs in different disease models. Results showed that in addition to controlling TH1 and TH2responses, c-Maf served a previously unknown, more dominant role in the EAE model, beyond IL-10 expression, by regulating the balance of TH17 cell responses (Rorc) and Foxp3+ Treg cell responses To identify the molecular mechanisms whereby c-Maf affects gene regulation in CD4+ T cells in vivo, the author used the assay for transposase-accessible chromatin plus sequencing(ATAC-seq) to reveal functionally active genomic regions. Further study showed that IL-2 is a c-Maf target. The decreased expression of Rorc observed inMaf-deficient TH17 cells were caused indirectly via the action of IL-2, since this effect was abolished by neutralization of IL-2.
This paper demonstrated abroad yet context-specific role for c-Maf in regulating gene expression that allows each type of T cell effector immune response to occur in a controlled yet effective manner and suggested new potential drug target for different disease .
https://www.nature.com/articles/s41590-018-0083-5.pdf
Edited by Qianru Huang
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