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  • Review Article
  • Published:

Transcriptional control of effector and memory CD8+ T cell differentiation

Nature Reviews Immunology volume 12, pages 749–761 (2012)Cite this article

Subjects

Key Points

  • During an infection, T cells can differentiate into multiple types of effector and memory T cell that help to mediate pathogen clearance and provide long-term protective immunity.

  • Hypothetical models — known as the separate-precursor, decreasing-potential, signal-strength and asymmetric cell fate models — help to explain the generation of heterogeneous effector and memory T cells.

  • The strength and duration of signals 1, 2 and 3 (mediated by antigen, co-stimulatory molecules and cytokines, respectively) can influence effector T cell fate decisions.

  • The expression or activity of counter-regulatory transcription factors functions in a graded manner to regulate effector and memory T cell differentiation. Such transcription factor pairs include: T-bet and eomesodermin; B lymphocyte-induced maturation protein 1 (BLIMP1) and B cell lymphoma 6 (BCL-6); inhibitor of DNA binding 2 (ID2) and ID3; and signal transducer and activator of transcription 3 (STAT3) and STAT4.

  • Cellular metabolic fitness and metabolic signalling pathways — mainly the phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)–forkhead box O (FOXO) pathways — regulate T cell differentiation, effector function and lifespan.

  • Cytokine signalling and transcriptional programmes control the progressive differentiation or functional maturation of memory T cells during the effector-to-memory cell transition.

  • During chronic infection, phenotypic, functional and transcriptomic diversification of CD8+ T cells occurs over multiple rounds of stimulation.

Abstract

During an infection, T cells can differentiate into multiple types of effector and memory T cells, which help to mediate pathogen clearance and provide long-term protective immunity. These cells can vary in their phenotype, function and location, and in their long-term fate in terms of their ability to populate the memory T cell pool. Over the past decade, the signalling pathways and transcriptional programmes that regulate the formation of heterogeneous populations of effector and memory CD8+ T cells have started to be characterized, and this Review discusses the major advances in these areas.

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Figure 1: Kinetics of a T cell response and distribution of memory cell potential.
Figure 2: Models for generating effector and memory T cell heterogeneity.
Figure 3: Graded activity of transcriptional programmes that control effector and memory T cell differentiation.
Figure 4: Model for the metabolic regulation of effector and memory T cell differentiation.

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Acknowledgements

We thank the members of the Kaech laboratory for helpful comments and discussions. This work was supported by grants to S.M.K. from the US National Institutes of Health (grants R01AI074699, RO1AI066232, R21AI097767 and R21AI081150) and from the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, 06520, Connecticut, USA

    Susan M. Kaech & Weiguo Cui

  2. Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, 20815, Maryland, USA

    Susan M. Kaech

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  1. Susan M. Kaech
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Correspondence to Susan M. Kaech.

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Glossary

Type 1 responses

Coordinated immune responses that occur following viral or intracellular bacterial infection. They are usually characterized by the rapid induction of innate cytokines such as interleukin-12 and interferons and the development of T helper 1 (TH1) cells and cytotoxic T cells.

T follicular helper cells

(TFH cells). A distinct subset of CD4+ helper T cells that are CXCR5hiPD1hi. These cells primarily migrate into germinal centres following immunization, where they regulate the development of antigen-specific B cell immune responses.

Central memory T cells

(TCM cells). A subset of memory T cells that are normally CD62LhiCCR7hi and that home to the secondary lymphoid organs.

Effector memory T cells

(TEM cells). A subset of memory T cells that are normally CD62LlowCCR7low and that reside in non-lymphoid tissues.

Cellular barcoding

A tool for clonal analysis. Retroviral vectors with random sequences (that are referred to as 'barcodes') are transduced into progenitor cells. On integration, each vector introduces a unique, identifiable and heritable mark into the host cell genome, allowing the clonal progeny of each cell to be tracked over time.

Asymmetric cell division

A process that produces two daughter cells with different cellular fates. This is in contrast to symmetric cell division, which gives rise to daughter cells of equivalent fates.

T-box transcription factors

A family of transcription factors characterized by their homologous T-box DNA-binding domain.

Mammalian target of rapamycin

(mTOR). A serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription. mTOR belongs to the phosphoinositide 3-kinase (PI3K)-related kinase protein family. The PI3K–AKT–mTOR pathway is activated by T cell receptor signalling and sustained by pro-inflammatory cytokines such as IL-2 and IL-12.

WNT

A family of glycoproteins related to the Drosophila melanogaster protein Wingless, a ligand that regulates the temporal and spatial development of the embryo. WNT-mediated signalling has been shown to regulate cell fate determination, proliferation, adhesion, migration and polarity during development. In addition to their crucial role in embryogenesis, WNT proteins and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colon cancers. WNT signalling activates TCF and LEF family transcription factors by stabilizing their co-activator, β-catenin, and mobilizing this factor from the cytoplasm to the nucleus.

E protein transcription factors

Key transcriptional regulators that control many aspects of lymphocyte development. E proteins bind as homodimers or heterodimers to DNA at their canonical E box sites, where they function as transcriptional activators or repressors. There are four E proteins in mammals, namely E47, E12, HEB and E2-2.

JAK–STAT signalling

A signalling pathway that transmits information from cell-surface receptors for specific chemical signals outside the cell to gene promoters in the DNA in the cell nucleus, which causes DNA transcription and activity in the cell.

Hyper-IgE syndrome

(Also known as Job's syndrome). A heterogeneous group of immune disorders caused by autosomal dominant mutation of STAT3. It is characterized by recurrent infections and very high concentrations of the serum antibody IgE.

mTORC1

(mTOR complex 1). A complex composed of mTOR, regulatory associated protein of mTOR (RAPTOR), LST8 (also known as GβL), RAS40 and DEPTOR. This complex is characterized by the classic features of mTOR, in that it functions as a nutrient, energy and redox sensor and controls protein synthesis.

mTORC2

(mTOR complex 2). A complex composed of mTOR, rapamycin-insensitive companion of mTOR (RICTOR), LST8 and SAPK-interacting protein 1 (SIN1). mTORC2 phosphorylates the serine/threonine protein kinase AKT at a serine residue (S473). mTORC2 has also been shown to function as an important regulator of the cytoskeleton.

Hayflick limit

The number of times that a normal cell population will divide before it stops and enters a phase of senescence.

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Kaech, S., Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12, 749–761 (2012). https://doi.org/10.1038/nri3307

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