Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

Śledzińska, Anna; Mucha, Maria Vila de; Bergerhoff, Katharina; Hotblack, Alastair; Demane, Dafne Franz; Ghorani, Ehsan; Akarca, Ayse U.; Marzolini, Maria A V; Solomon, Isabelle; Vargas, Frederick Arce; Pulé, Martin; Ono, Masahiro; Seddon, Benedict; Kassiotis, George; Ariyan, Charlotte E.; Korn, Thomas; Marafioti, Teresa; Lord, Graham M.; Stauss, Hans J.; Jenner, Richard G.; Peggs, Karl S.; Quezada, Sergio A.

doi:10.1016/j.immuni.2019.12.007

Cited by 150 publications

(134 citation statements)

References 66 publications

(86 reference statements)

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“…B cells, and ~75% of DLBCL tumors, constitutively express MHC-II, and nearly all cell lineages can express class II after exposure to IFNg and other cytokines. CD4+ T cells can participate in tumor clearance by directly lysing tumor cells as well as by enhancing tumor lysis by other immune cell types (Alspach et al, 2019;Sledzinska et al, 2020), and MHC-II may represent an important target for non-conventional CD8+ T cells that can be induced by specific viral vectors (Hansen et al, 2013). As MHC-II may be critically important for DLBCL patient survival (Ennishi et al, 2019), the dual role of some genes we identified is likely clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

Dersh

Phelan

Gumina

et al. 2020

Preprint

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Section: Discussionmentioning

confidence: 99%

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

Dersh

Phelan

Gumina

et al. 2020

Preprint

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“…Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of T-bet and Blimp-1. While T-bet ablation restricted the production of IFN-γ, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting that two independent programmes required for the polyfunctionality of tumour-reactive cytotoxic CD4 + T cells [ 144 ]. In addition, blocking IFN α and β receptor 1 (IFNAR1) on Tregs significantly decreases both the Tregs immunosuppressive function and myeloma progression.…”

Section: Tumour Immunotherapy Strategies Targeting Tregsmentioning

confidence: 99%

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

et al. 2020

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Regulatory T cells (Tregs) characterized by the expression of the master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance of tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot in the field. However, Tregs are also essential for the maintenance of the immune tolerance of the body and share many molecular signalling pathways with conventional T cells, including cytotoxic T cells, the primary mediators of tumour immunity. Hence, the inability to specifically target and neutralize Tregs in the tumour microenvironment without globally compromising self-tolerance poses a significant challenge. Here, we review recent advances in characterizing tumour-infiltrating Tregs with a focus on the functional roles of costimulatory and inhibitory receptors in Tregs, evaluate their potential as clinical targets, and systematically summarize their roles in potential treatment strategies. Also, we propose modalities to integrate our increasing knowledge on Tregs phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Finally, we propose possible treatment strategies that can be used to develop Treg-targeted therapies.

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“…However, some mature CD4 T cells, cytotoxic CD4 T cells (CD4-CTLs or Th-CTLs), may act similarly as cytotoxic CD8 T cells in killing their target cells through the secretion of granzyme B and perforin but in an MHCII-restricted manner [13][14][15]. The transcriptional factor Eomes (a T-box transcription factor critical for the development of functional natural killer (NK) and CD8 T cells), T-bet, and Blimp1 are critical for inducing the expression of cytotoxicity-associated genes in CD4-CTLs [16][17][18]. Similar to CD8 T cells, CD4-CTLs display increased Runx3 but reduced ThPOK expression [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Zhu

2020

IJMS

198

138

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The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

Cited by 150 publications

References 66 publications

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

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