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The multifaceted role of CD4+ T cells in CD8+ T cell memory

Nature Reviews Immunology volume 16, pages 102–111 (2016)Cite this article

Subjects

Key Points

  • Following immunization, CD4+ T cells promote the induction of a robust primary CD8+ T cell response through numerous mechanisms, including licensing of dendritic cells (DCs) and promoting the interaction between DCs and CD8+ T cells.

  • CD4+ T cells regulate the secondary responsiveness of CD8+ T cells during immunization through suppression of TNF-related apoptosis-inducing ligand (TRAIL) through a process dependent on licensing of DCs to produce interleukin-15 (IL-15) and autocrine secretion of IL-2 by CD8+ T cells.

  • Following infection, CD4+ T cell help is necessary for the induction of a memory CD8+ T cell pool capable of mediating protective immunity but is largely dispensable for a robust primary response.

  • Regulatory T (TReg) cells act during the resolution phase of infection to protect CD8+ T cells from inflammatory signals and promote the survival of a CD8+ T cell pool capable of robustly expanding upon secondary infection.

  • CD4+ T cell help promotes the induction of tissue-resident memory CD8+ T cells during mucosal infection through guidance of CD8+ T cells into a microenvironment where they can become exposed to the signals necessary for their continued maintenance within the tissue.

  • During chronic infection, effector CD4+ T cells support the maintenance of functional CD8+ T cells through secretion of IL-21, whereas TReg cells dampen the CD8+ T cell response through suppression of DCs.

Abstract

Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4+ T cells are essential in the formation of protective memory CD8+ T cells following infection or immunization. However, until recently, the mechanisms by which CD4+ T cells act to support memory CD8+ T cell development following infection were unclear. Here, we discuss recent studies that provide insight into the multifaceted role of CD4+ T cells in the regulation of memory CD8+ T cell differentiation.

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Figure 1: CD4+ T cell help to CD8+ T cells during immunization.
Figure 2: TReg cells promote memory CD8+ T cell maturation during viral infection.
Figure 3: CD4+ T cell help to CD8+ T cell during mucosal infection.
Figure 4: Temporal model of CD4+ T cell help during infection.

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Acknowledgements

The authors thank all members of the Kaech and Craft laboratories for discussions and critical reading of the manuscript. They are supported by the US National Institutes of Health (RO1AI066232 and R01AI074699 to S.M.K.; R01AR40072, P30AR053495 and R21AR063942 to J.E.C.; T32AI07019 and F31AG07777 to B.J.L.) and the Howard Hughes Medical Institute (S.M.K. and B.J.L.).

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Authors and Affiliations

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

    Brian J. Laidlaw, Joseph E. Craft & Susan M. Kaech

  2. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, 94143, California, USA

    Brian J. Laidlaw

  3. Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Joseph E. Craft

  4. Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, 2081, Maryland, USA

    Susan M. Kaech

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Correspondence to Brian J. Laidlaw.

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PowerPoint slides

Glossary

Cross-presentation

The ability of certain antigen-presenting cells (primarily dendritic cells) to redirect exogenous antigens to the MHC class I pathway, allowing for the stimulation of naive CD8+ T cells by these cells. This process is important for the induction of immune responses against most tumours and viruses that do not typically infect antigen-presenting cells.

'Helpless' CD8+ T cells

CD8+ T cells that have undergone activation and differentiation in the absence of CD4+ T cell-dependent stimulation ('help').

Activation-induced cell death

A process by which fully activated T cells undergo programmed cell death following binding of the T cell receptor by antigen or mitogen. Cell death occurs through the engagement of death receptors (such as FAS or the tumour-necrosis factor family receptors) or the production of reactive oxygen species.

Functional exhaustion

A state of non-responsiveness of T cells resulting from chronic exposure to high levels of antigen marked by high expression of inhibitory receptors. Exhausted cells are impaired in their ability to proliferate and secrete cytokines, compromising their ability to control pathogen load.

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Laidlaw, B., Craft, J. & Kaech, S. The multifaceted role of CD4+ T cells in CD8+ T cell memory. Nat Rev Immunol 16, 102–111 (2016). https://doi.org/10.1038/nri.2015.10

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