Review Article | Published:

Recent developments in the transcriptional regulation of cytolytic effector cells

Abstract

Transcription factors have a profound influence on both the differentiation and effector function of cells of the immune system. T-bet controls the cytotoxicity of CD8+ T cells and the production of interferon-γ, and it also affects the development and function of natural killer cells and natural killer T cells. Other factors such as eomesodermin, MEF, ETS1 and members of the interferon-regulatory factor family also contribute to the effector function of immune cells. In this review, we focus on recent studies that have shed light on the transcriptional mechanisms that regulate cellular effector function in the immune system.

Key Points

  • Typically, transcription factors are modular proteins that regulate the expression of genes through their binding to DNA regulatory elements. They can either activate or repress the transcription of genes by RNA polymerase.

  • Cytolytic effector cells of the immune system include CD8+ T cells and natural killer (NK) cells. They mediate the killing of target cells through the exocytosis of cytolytic granules that contain perforin and granzymes or by activation of apoptosis through the FAS–FAS ligand (FASL) pathway.

  • NK cells are components of the innate immune system and develop with pre-formed cytotoxic granules; after maturation, they can attack and kill target cells within 20–30 minutes. By contrast, CD8+ T cells are components of the adaptive immune system and require activation through stimulation of the T-cell receptor for several days before they show cytotoxicity.

  • Transcription factors have crucial roles in both the development and the effector function of cytolytic effector cells, such as CD8+ T cells and NK cells. Some transcription factors — for example, SP1 transcription factor and nuclear factor-κB — are widely expressed by many cell types and drive the expression of several genes. By contrast, tissue-specific factors such as the T-box factors T-bet and eomesodermin (EOMES) have been shown to have important roles in these cytolytic subsets. Such tissue-specific factors function as master regulators to initiate specific gene-expression programmes.

  • T-bet is expressed by the cytolytic cell lineages — CD8+ T cells, NK cells and natural killer T (NKT) cells — as well as by CD4+ T helper 1 cells. The best-defined target gene of T-bet is the gene encoding interferon-γ (IFN-γ), but those encoding the cytolytic effector molecules granzyme B and perforin have also been shown to be direct targets. T-bet also has important roles in the regulation of IFN-γ production and cytotoxicity in the previously mentioned cell types.

  • EOMES has been shown to be highly expressed by CD8+ T cells and NK cells but not by CD4+ T cells and NKT cells. In addition, overexpression of EOMES has been shown to drive the expression of IFN-γ, perforin and granzyme B, thereby indicating that these genes are also direct targets of EOMES.

  • Other transcription factors — such as STAT1, STAT4, RUNX3, REL, MITF, C/EBP-γ, NEMO and IRF2 — also have important roles in the production of IFN-γ and cytotoxic molecules in these cell types. Absence of the ETS-family members ETS1 or MEF (myeloid ELF1 (E74-like factor 1)-like factor) results in defective NK-cell development and cytotoxicity, and MEF has been shown to directly regulate expression of the perforin gene.

  • The genes encoding perforin, granzyme B and FASL are regulated by multiple transcription factors, many of which are widely expressed. The ongoing challenges are to identify the tissue-specific transcription factors that are master regulators of expression of the cytolytic effector machinery and to understand how they interact with the other more-ubiquitously expressed transcription factors. In addition, identification of important regulatory elements in the promoters and upstream or downstream enhancer elements, together with assessment of the chromatin structure of these cytolytic genes in different cell types, provides mechanistic explanations for how the expression of these genes is controlled.

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Acknowledgements

Support was provided by grants from the National Institutes of Health (Bethesda, United States) and the Juvenile Diabetes Research Foundation (New York, United States). M.J.T. is supported by a Postdoctoral Fellowship from the Cancer Research Institute (New York). G.M.L. is a Medical Research Council (United Kingdom) Clinician Scientist.

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Correspondence to Laurie H. Glimcher.

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Competing interests

Laurie H. Glimcher is on the scientific advisory board of the Mannkind Corporation and on the corporate board of the Bristol-Myers Squibb Company. She has equity in both of these companies and has filed patents that have been licensed by Mannkind Corporation.

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DATABASES

Entrez Gene

EOMES

FASL

granzyme B

IFN-γ

perforin

T-bet

Glossary

TRANSACTIVATION

The process by which a transcription factor binds the promoter region of a gene and induces its transcription.

REPRESSION

The process by which a transcription factor binds the promoter region of a gene and inhibits its transcription.

T-BOX (TBX) TRANSCRIPTION FACTORS

A family of transcription factors that each contains a DNA-binding domain of 200 amino acids known as the T-box. These factors are usually involved in developmental programmes, and the founding member of the family is Brachyury. T-bet and eomesodermin are members of this family.

T HELPER 1 (TH1)-CELL

The definition of a CD4+ T cell that has differentiated into a cell that produces the cytokines interferon-γ and tumour-necrosis factor.

T-BOX DNA-BINDING DOMAIN

A 200-amino-acid DNA-binding domain found in all members of the T-box family. This domain binds a consensus sequence found in the promoter regions of genes.

OT-1 TCR-TRANSGENIC MICE

Transgenic mice that have a T-cell receptor specific for an MHC-class-I-restricted peptide derived from ovalbumin. T cells from these mice can be activated in an antigen-specific manner either in vitro or in vivo.

CHROMIUM-RELEASE ASSAY

An assay that determines the activity of cytotoxic cells on the basis of their ability to lyse target cells labelled with radioactive chromium. The amount of radioactivity released is proportional to the number of target cells that are killed by the cytolytic cells added to the culture.

RAT INSULIN PROMOTER (RIP)–LCMV TRANSGENIC MODEL

A transgenic mouse model of type 1 diabetes in which peptides derived from lymphocytic choriomeningitis (LCMV) are expressed in the pancreas under the control of RIP. Infection of the mouse with LCMV leads to the development of diabetes as a result of infiltrating CD8+ effector T cells.

CHROMATIN IMMUNOPRECIPITATION

An experimental technique that analyses direct binding of an endogenous transcription factor to chromatin by fixation with formaldehyde followed by immunoprecipitation with a transcription-factor-specific antibody. Gene-specific enrichment is then assessed by polymerase chain reaction analysis of the immunoprecipitated DNA.

Vα14i NKT CELLS

The most abundant subset of natural killer T (NKT) cells. They have a rearrangement of the T-cell receptor (TCR) variable-gene segment Vα14 to the joining-region segment Jα18 to form an invariant complementarity-determining region. The resulting TCR is known as Vα14 invariant (Vα14i). This TCR is autoreactive to CD1d, and Vα14i NKT cells respond strongly to α-galactosylceramide (α-GalCer) presented in the context of CD1d.

DNASE I FOOTPRINTING ANALYSIS

An in vitro experimental technique for identifying the DNA sequence to which a transcription factor binds. A short end-labelled fragment of the DNA sequence of interest is incubated with nuclear extract and then digested with a low concentration of DNase I. The digested DNA is then recovered from the reaction and resolved on a polyacrylamide gel, together with a sequencing reaction using the same DNA fragment as the template. The regions bound by proteins are protected from DNase I digestion and appear as blank areas on the gel, and the exact protein-bound sequence can be determined by comparing the location of the blank areas with that of the sequencing reaction.

SV40 TAG REPORTER

A reporter gene consisting of the SV40 virus large T antigen — a multifunctional 85 kDa protein that is the sole viral protein required for SV40 replication and causes malignant transformation of susceptible cells.

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Further reading

Figure 1: Main transcriptional pathways in CD8+ effector T cells.
Figure 2: Overview of the transcriptional pathways in natural killer cells.
Figure 3: General organization of the perforin, granzyme B and FAS ligand gene promoters.