Summary The discovery of the specification of CD 4 + helper T cells to discrete effector ‘lineages’ represented a watershed event in conceptualizing mechanisms of host defense and immunoregulation. However, our appreciation for the actual complexity of helper T‐cell subsets continues unabated. Just as the Sami language of Scandinavia has 1000 different words for reindeer, immunologists recognize the range of fates available for a CD 4 + T cell is numerous and may be underestimated. Added to the crowded scene for helper T‐cell subsets is the continuously growing family of innate lymphoid cells ( ILC s), endowed with common effector responses and the previously defined ‘master regulators’ for CD 4 + helper T‐cell subsets are also shared by ILC subsets. Within the context of this extraordinary complexity are concomitant advances in the understanding of transcriptomes and epigenomes. So what do terms like ‘lineage commitment’ and helper T‐cell ‘specification’ mean in the early 21st century? How do we put all of this together in a coherent conceptual framework? It would be arrogant to assume that we have a sophisticated enough understanding to seriously answer these questions. Instead, we review the current status of the flexibility of helper T‐cell responses in relation to their genetic regulatory networks and epigenetic landscapes. Recent data have provided major surprises as to what master regulators can or cannot do, how they interact with other transcription factors and impact global genome‐wide changes, and how all these factors come together to influence helper cell function.

Innate lymphoid cell

T helper cell

10.1111/imr.12208

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Citations (85)

Janus Kinases and STAT Family Transcription Factors: Their Role in the Function and Development of Lymphoid Cells

Tammy P. Cheng Jérôme Galon Roberta Visconti Massimo Gadina John J. O’Shea

This chapter focuses on only two structurally related families of cytokine receptors, Type I and Type II receptor families, since their receptor phosphorylation leads to the activation of the Stat family of transcription factors. Members of these two receptor families have no intrinsic tyrosine kinase activity and utilize Janus kinases (Jaks) to initiate extracellular signaling. The structure and function of various Jaks and Stats are the focus of this review; the latter in particular are emphasized in accordance with the transcription factor theme of this book.

Janus kinase 1

Cytokine receptor

10.1002/0471223883.ch15

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Inter-regional differences in acute coronary syndrome trials

European Heart Journal (2000)

John J. O’Shea

10.1053/euhj.2000.2121

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Citations (16)

The Janus kinases (Jaks)

Genome biology (2004)

Kunihiro Yamaoka Pipsa Saharinen Marko Pesu Vance Holt Olli Silvennoinen

The Janus kinase (Jak) family is one of ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2). Birds, fish and insects also have Jaks. Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain, and they each bind cytokine receptors through amino-terminal FERM (Band-4.1, ezrin, radixin, moesin) domains. Upon binding of cytokines to their receptors, Jaks are activated and phosphorylate the receptors, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (Stat) family. Mutations of the Drosophila Jak (Hopscotch) have revealed developmental defects, and constitutive activation of Jaks in flies and humans is associated with leukemia-like syndromes. Through the generation of Jak-deficient cell lines and gene-targeted mice, the essential, nonredundant functions of Jaks in cytokine signaling have been established. Importantly, deficiency of Jak3 is the basis of human autosomal recessive severe combined immunodeficiency (SCID); accordingly, a selective Jak3 inhibitor has been developed, forming a new class of immunosuppressive drugs.

Tyrosine kinase 2

Glycoprotein 130

Janus kinase 1

Cytokine receptor

Janus kinase 3

Protein kinase domain

10.1186/gb-2004-5-12-253

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Citations (573)

Table of Contents

The Journal of Allergy and Clinical Immunology In Practice (2023)

Ellen Van Den Bogaard Peter M. Elias Elena Goleva Evgeny Berdyshev Jos P.H. Smits

Table (database)

10.1016/s2213-2198(23)00362-8

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A critical CTCF binding site of the Ifng-Il22 locus specifies cytokine expression and finetunes immune response

The Journal of Immunology (2021)

Han‐Yu Shih Chunhong Liu Ping Wang Sadie Signorella William Montgomery

Abstract Precise control of cytokine milieu plays an essential role in homeostasis and diseases, and dysregulated cytokine production leads to undesired inflammation and autoimmunity. Interferon gamma (IFN-γ) and interleukin-22 (IL-22), two key cytokines for against intracellular and extracellular pathogens, respectively, evolutionarily resides in close genomic proximity. Notably, these genes are exclusively expressed in type I and type III lymphoid cells via complex epigenomic regulation that remains largely unknown. Our ATAC-seq, ChIP-seq and PollI ChIA-PET datasets revealed a CTCF binding site 70kb upstream of Ifng setting a boundary of the enhancer landscapes. Therefore, we proposed that this CTCF site segregates Ifng and Il22gene enhancers for lineage-specific gene regulation. To investigate whether this CTCF binding contributes to bifurcated cytokine gene regulation at the Ifng-Il22 locus, we deleted this 17bp Ifng (−70kb)CTCF site in mice using a CRISPR strategy. We found that Ifng (−70kb)CTCFdel CD4+ T cells revealed deficiency in initial Th1 cell differentiation. Using single cell RNA-seq and Toxoplasma gondii infection as a model for type I immune response in vivo, we identified aberrant Th17 differentiation and increased T cells prolifereation in Ifng (−70kb)CTCFdel mice. To further understand the molecular mechanism, we measured CTCF associated loop formation in pre-differentiated Naïve CD4+ T cells and interestingly, this Ifng (−70kb)CTCF site formed a loop with a CTCF-enriched region on the other side of Il22 gene. Our data provide a novel pre-determined mechanism that prevents cross activation for IFN-γ enhancers to target IL-22 prior to differentiation.

CTCF

Jurkat cells

10.4049/jimmunol.206.supp.53.13

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Citations (1)

Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity

Immunity (2015)

Kiyoshi Hirahara Atsushi Onodera Alejandro V. Villarino Michael Bonelli Giuseppe Sciumè

STAT1

Chromatin immunoprecipitation

Transcription

STAT4

10.1016/j.immuni.2015.04.014

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Citations (139)